The Role of Lymphadenectomy in the Surgical Treatment of Esophageal and Gastric Cancer

The Role of Lymphadenectomy in the Surgical Treatment of Esophageal and Gastric Cancer Introduction Few topics in surgery generate as much controversy and heated debate as the role of lymphadenectomy in cancer. Fundamental to this issue is the biological understanding of cancer itself and the significance of lymph node spread during the natural history of a tumor. As the fields of biology and medicine have developed over the centuries, our understanding of carcinogenesis has changed radically. In this review, the concepts of cancer biology will be reviewed, beginning with a historical foundation and ending in contemporary thought. Progress in our understanding of the lymphatic system and the potential therapeutic value of removing lymph nodes in the treatment of patients with upper gastrointestinal (GI) malignancy will be emphasized. As surgery for esophageal and gastric cancer has evolved, particularly in the latter half of the 20th century, the clinical biology of these diseases has been determined. Based on this evidence and from recent clinical trials, an understanding of the role of lymphadenectomy in the surgical therapy of esophageal and gastric cancer will be analyzed.

History The root of the modern word cancer has been ascribed to Hippocrates (460-370 BC), who used the Greek words carcinos and carcinoma, which means crab. This choice was based on the observations of outward growth through fingerlike projections of most solid tumors, which resembled the appearance of a crab. Cancer, the Latin term, was used later by the Roman physician Celsus (28-50 BC). Thus, the origin of the word cancer reflected the concept that a tumor is locally progressive and spreads outward from the primary lesion. It follows that this fundamental premise formed the basis of the historical approach to cancer treatment—localized therapy. For most of the history of cancer treatment (its earliest descripCurr Probl Surg 2012;49:471-515. 0011-3840/$36.00 ⫹ 0 http://dx.doi.org/10.1067/j.cpsurg.2012.04.003

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tions to the mid-20th century), local therapy was the only modality available for the treatment of cancer. Indeed, the oldest known description of cancer treatment, attributed to the ancient Egyptians and written in the Edwin Smith Papyrus circa 3000 BC, entails local cauterization of breast tumors. Even though resection and/or local control was the only treatment modality available before the advent of chemotherapy and radiation therapy, it was long recognized that the cancerous process often involved an area beyond that of the focal tumor. The experience that resection alone could not cure many patients of their cancer, particularly in the era of rudimentary surgical technology and presentation at the late stages of disease, repeatedly reinforced this concept. Galen (131-203 AD) postulated the humoral theory of carcinogenesis, which held that tumors formed by the abnormal pooling of black bile.1 Based on this theory, the tumor and its associated organ and surrounding tissue were affected, and removal of all of it was necessary to eradicate the black bile. Removal of the tumor itself was not thought to be successful. The humoral theory dominated medical thinking until the 16th century, when concepts changed such that the etiology of tumors was thought to be from a source outside the body, rather than from the inside. Galen’s hypothesis was followed by the mineral theory of carcinogenesis espoused by Paracelsus (1493-1541), postulating that tumors formed because of the abnormal entrance of certain types of minerals. This theory of cancer was ultimately replaced by the lymphatic theory of carcinogenesis under the influence of William Harvey’s publication of blood circulation in the 18th century. Under the lymphatic theory of carcinogenesis, it was thought that tumors formed when blood exited the circulatory system and stasis allowed it to solidify. Again, the concept that the local tumor was only a part of a much larger abnormal portion of the body was well established. John Hunter wrote that the surgeon “should also take away some portion of the surrounding substance in which a diseased disposition may probably have been excited.”1,2 A major advance in the understanding of cancer was the emergence of cell theory in the 19th century. This postulated that the cell is the basic unit of life, and that all cells are derived from other cells. Under this conceptual framework, the unicellular origin of cancer was established, and ushered in the modern concepts of carcinogenesis. Rather than abnormal accumulation of humors, mineral, or lymph, tumors began as individual cells and grew over time. Virchow postulated that the underlying cause of the cell to become cancerous was related to inflammation, an interesting historical reference considering the primary role inflammation is once again taking in our modern understanding of carcinogenesis.3 472

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FIG 1. The mechanistic of “Halstedian” paradigm or cancer spread. (Color version of figure is available online.)

Eventually, the cancer cells replicated allowing the tumor to spread into the local environment before breaking free and entering the circulation to deposit in distant organs. Based on this assumption, surgical resection of the tumor early in its course, before it spread to distant organs, would cure the patient. Although significant advances in the biological understanding of carcinogenesis were occurring, surgery as a discipline did not make significant progress until the development of ether anesthetic by William Morton in 1846 and the acceptance of Semmelweis and Lister’s principles of asepsis between 1840 and 1860. With these critical developments in place, the field of modern surgery crystallized, and the next century would witness tremendous growth in surgical oncology with refinements in surgical technique and increasing understanding of cancer biology as it related to surgical resection. The principles of surgical oncology at the turn of the 20th century were founded on the concept that a focal tumor sequentially grows outward from the primary lesion to enter the lymphatic system to deposit inside lymph nodes, and from the lymph nodes, the metastatic cells then enter the bloodstream and lead to distant metastases. This concept was promoted by William Handley and the mechanistic or “Halstedian” paradigm of cancer biology laid the foundation for the en bloc surgical resection, exemplified by the radical mastectomy for breast cancer advocated by William Halstead and Willie Mayer (Fig 1). The underlying principle is that the primary tumor and all of its surrounding lymphatic tissue must be removed to allow for effective treatment, as it would not only remove the tumor but also the cells deposited in the lymph nodes. It Curr Probl Surg, August 2012

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was believed that if lymph node metastases were left behind, these would in turn metastasize elsewhere and spread to distant organs. Fundamental to this concept was the assumption that metastases could metastasize. This paradigm dominated surgical oncology well into the 20th century and remains a viable concept today. This sentiment was underscored in a statement written by the well-known colorectal surgeon B.G.A. Moynihan in 1908, who commented, “The surgery of malignant disease is not the surgery of organs; it is the anatomy of the lymphatic system.”4 At that time, surgery was the only known treatment modality for cancer, and it was believed that the bigger the resection, the better the chance at cure. Widespread acceptance of the Halsted concepts of cancer biology during most of the 20th century, coupled with the lack of nonsurgical treatment alternatives, led to the common use of radical resections to affect cure. Within this paradigm, the classic radical operations of modern surgery were developed, from radical neck dissections to abdominoperineal resections. In contrast to breast cancer, where most of the resection is superficial and outside of the body cavity, successfully operating on the stomach and esophagus required the development of additional advances in surgical and perioperative management before these principles could be applied. Thus, radical resections for esophageal and gastric cancer did not emerge until the 1950s and 1960s. Although successful gastrectomy for cancer was first performed by Christian Billroth in 1881, and esophagectomy for cancer by Franz Torek in 1913, it was not until the 1940s that surgeons began to understand lymph node anatomy, patterns of metastases, and recurrence rates of upper GI cancer.5,6 As such, en bloc resections with radical lymphadenectomy for gastrectomy were not reported until 1951 (Mcnear) and for esophagectomy in 1963 (Logan).7 This paradigm of the en bloc resection with radical lymphadenectomy remained largely unquestioned until the 1960s, when large clinical trials in breast cancer began to indicate that lesser resections resulted in survival rates similar to those for patients who had radical operations. Furthermore, it was observed that systemic disease could occur in the absence of lymph node metastases, and the emphasis on only local control for optimal survival began to erode. A new paradigm emerged, spearheaded by the head of the National Surgical Adjuvant Breast and Bowel Project, Bernard Fisher, and became known as the systemic or “Fisher” paradigm (Fig 2). Under this paradigm, cancer does not progress in a sequential orderly manner from the tumor to the lymph nodes to the bloodstream; rather, metastatic cells from the primary tumor can invade both the lymphatic system and hematogenous circulation simultaneously, even at early stages of tumor growth. The systemic paradigm emphasizes 474

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FIG 2. The systemic or “Fisher” paradigm of cancer spread. (Color version of figure is available online.)

the intrinsic biological behavior of the primary tumor, which in turn dictates the prognosis and outcome of the patient. Some researchers have referred to this as biological determinism, in which lymph node metastases is just 1 of several parameters reflecting the aggressive biology of the tumor. As famously proclaimed by Fisher, “lymph node metastasis is an indicator, not a governor of prognosis.”8 It is important to note that this paradigm shift regarding the role of surgery and lymphadenectomy for cancer corresponded with several key developments in the latter half of the 20th century. First, the development of effective chemotherapy introduced a new treatment modality that could complement or even substitute for surgical resection. For the first time in the history of medicine, systemic chemotherapy allowed clinicians to treat metastatic disease, and it became apparent that this could play a critical role in the overall outcome when compared with local or regional treatment alone. If microscopic cancer was left behind with a lesser resection, chemotherapy could potentially control it also. Second, research in cancer biology in the 1970s began to strengthen the seed and soil hypothesis, which was first outlined by Stephen Paget in 1889. This hypothesis dictates that a metastatic tumor cell (the “seed”) does not have a pluripotential capacity to spread everywhere, but that each metastatic Curr Probl Surg, August 2012

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cell possesses specific biological traits that allow it to establish itself in a viable manner in 1 particular organ. Equally important, the recipient organ (the “soil”) in turn must possess specific characteristics to allow this tumor cell to grow. Thus, a tumor cell that metastasizes to a lymph node could only establish itself in that node, and even if this cell could enter the systemic circulation with access to distant organs, it would not have the capacity to survive. In other words, metastases do not have the ability to metastasize. According to this logic, because patients most often die of metastases to distant organs, and not from metastatic lymph nodes, removing these nodes will not have a significant impact on patient survival. Third, the concept of cancer screening began to mature in the 1970s, which allowed for the detection of smaller tumors earlier in their natural history. In breast cancer treatment, screening mammography had a profound effect on the detection of smaller cancers, which began to improve outcomes. The application of radical resections developed in Halstead’s time appeared to be overkill for the smaller cancers being detected in modern times. One effect of earlier diagnosis of cancer was that as smaller tumors began to be resected with the advent of screening, surgical resection alone frequently cured the patient. It became apparent that the systemic paradigm was not entirely accurate, as small tumors should be accompanied by systemic disease despite local resection if they were truly invading the systemic circulation simultaneously with the lymphatic system. However, experience with the complete resection of these earlier and smaller tumors frequently resulted in disease-free survival, indicating that when these tumors were caught within a certain window of time, systemic spread was not present. In the 1980s, a new conceptual framework emerged that was essentially a combination of both the Halsted and Fisher paradigms and emphasized the spectrum of cancer biology (Fig 3). According to this hybrid concept, the biology of the tumor is still the ultimate governor of survival, but it is dependent on the natural history of the tumor at the time of diagnosis and treatment. Early in its timeline, a tumor has cells that can invade the lymphatics and survive in the regional lymph nodes; however, with further genetic alterations, the tumor gains the ability to spread metastatic cells into distant organs through the systemic circulation. Furthermore, some tumors genetically gain the ability to invade systemically right from the outset. This paradigm preserves Paget’s seed and soil hypothesis that metastatic cells in the lymph nodes do not have the capacity to subsequently invade distant organs and rests on the fact that there is a 476

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FIG 3. Modern concepts of cancer biology focusing on the observation that there is a spectrum of behavior within tumor types and within each neoplastic lesion. (Color version of figure is available online.)

spectrum of tumor biology that allows different types of metastatic behavior. As our understanding of the biology of cancer has evolved over time, so has our opinion of the role of surgery itself. When cancer was thought to progress in an orderly mechanistic fashion, the role of surgery was to remove the tumor and its local or regional involvement through large resections. As the systemic nature of cancer became more accepted, adjuvant systemic therapy emerged and tumors began to be detected earlier, surgery was relegated as 1 of several cornerstones of treatment, primarily for local control. Currently, there is evidence to support both paradigms, as outlined in the spectrum model of cancer. As research into the biology of cancer has progressed, recognition of the biological uniqueness of an individual tumor has become paramount. Traditional parameters such as size or nodal involvement are increasingly becoming supplemented by measurements of a tumor’s individual biological characteristics, such as gene expression patterns, to guide surgical and nonsurgical treatment and to prognosticate outcome. Although the lymphatic system was first described by the ancient Greeks in the form of lacteals of a dog mesentery, the relationship to cancer biology was not established until the 19th century. Lymphatics were first systematically studied in humans during the Renaissance in the 1600s, and the term lymphatic was first used by Thomas Bartholin in 1653. At that time, the function of lymphatics and lymph nodes had not been established. William Harvey’s theory of the circulation was pubCurr Probl Surg, August 2012

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FIG 4. Percentage of esophageal and breast cancer patients presenting with local, regional, or systemic disease. (Reprinted with permission from Williams and colleagues.9)

lished in 1628, and the connection between the circulatory system and lymphatic system was established with the discovery of the drainage of the thoracic duct into the venous system in 1651 by Jean Pecquet. In the 1700s, the lymphatic system was first described to function in the absorption of interstitial fluid, and in 1860, Virchow hypothesized that lymph nodes served as a filter system within the lymphatic system. This concept was adopted to cancer biology and fit into the mechanistic paradigm of cancer. The mechanical filtration of lymph nodes that was first introduced by Virchow was further supported by James Ewing in the 1920s, who postulated that tumor cells end up being lodged in lymph nodes and distant organs based on mechanical factors such as a low-flow environment.

Rationale and Patient Selection for Extended Lymphadenectomy As important as the evolving concepts of cancer biology have been over the past 100 years, it is also useful to consider the clinical perspective of cancer care. Conceptually, at the time of presentation to the clinician, solid tumors occur in 3, and only 3, possible forms (Fig 4). They can be localized to the organ in which it originated; they may be regional (ie, spread to regional lymph nodes but not beyond); or the tumor may be systemic. The degree of surgical resection (ie, lymphadenectomy) will not influence the outcome of the first or last of these circumstances, but may influence the outcome for those patients with regional disease. The controversy regarding radical lymphadenectomy lies not only in proving its benefits but also in the acceptance of the existence of regional disease. Proof positive of the clinical reality of regional disease lies in the multitude of Kaplan–Meier survival curves (Fig 5) in which there exists 478

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FIG 5. Kaplan–Meier curve of node-positive and node-negative patients with esophageal cancer. Note the long-term survival of a small, but significant, proportion of patients with positive nodes. (Reprinted with permission from Hagen and colleagues.10)

a small but real prevalence of patients with positive lymph nodes who have prolonged survival (cure). The prevalence of regional disease likely varies from cancer to cancer, and from decade to decade, but the fact that it occurs in some proportion of patients seems indisputable. Once this fact is accepted, then it follows that lymphadenectomy will improve survival in the population of patients with regional disease. The challenge then becomes accurately identifying such patients before surgery. The goal of performing an en bloc radical resection of the tumor and its surrounding tissue is to remove the tumor and all lymphatic tissue that may or may not harbor metastatic cells. With this reasoning, better survival would be expected with the greater number of lymph nodes removed (evidence for this outlined later in the text), and lymphadenectomy serves a therapeutic purpose. Doing so presupposes knowledge of metastatic patterns for a given tumor type, histology, and location (reviewed later in the text). Although lymph nodes in proximity of the primary tumor have the highest probability of involvement, the biology of lymph node metastases is in fact complex. In the 1960s, Ludwig advanced the concept of afferent and efferent lymphatics, and showed that bypass of the most proximal lymph nodes was possible and common.11 This experimental evidence indicated further that not all lymphatic drainage of a tumor passed through the lymph nodes and a significant portion could enter directly into the bloodstream. These data supported the concept that Curr Probl Surg, August 2012

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lymph nodes were not filters, but rather porous, with bypass routes available. Cine-photomicrographic experiments in the 1960s showed that tumor cells injected into animals could pass through small capillary beds, and that they do not necessarily lodge in them, providing further experimental support that systemic metastases may occur without nodal involvement.12 These experiments resurrected the seed and soil hypothesis of Paget and demonstrated just how rarely tumor cells are successful in the metastatic process; on average, 1 per 10,000 injected tumor cells survived and gave rise to metastases.8 It was also observed that the high prevalence of circulating tumor cells in patients with early disease often does not manifest in the development of systemic disease. This observation, now shown in numerous types of cancer, suggests that systemic seeding of the circulation can occur early in carcinogenesis. In the majority of cases, however, these circulating tumor cells never manifest in the form of distant metastases. Thus, even though tumor cells have the ability to detach, spread, and enter the bloodstream early and frequently, they do not have the capacity to establish themselves as metastatic lesions. In fact, recent progress in high fidelity DNA sequencing and other advanced technologies can now capture and/or identify circulating tumor cells and DNA, potentially leading to early blood-based diagnosis and detection of recurrence. Modern concepts hold that lymph nodes do not function primarily as filters, but rather are more important as a component of immune function. The following 4 main functions of the lymphatic system are considered: (1) absorption and return of interstitial fluid to the bloodstream, (2) transport of absorbed fatty acids from the intestine to the bloodstream, (3) exposure of lymphocytes to foreign antigens, and (4) mediating an immune response in either the humoral or cell-mediated pathways.13 Returning to the biological theories of carcinogenesis, adherence to the Fisher hypothesis of systemic disease at the time of diagnosis relegates the role of lymphadenectomy to staging and classification of the tumor, without regard to any therapeutic benefit. En bloc resection of lymph nodes is replaced by sampling, with the aim of simply determining whether the tumor has the ability to invade the regional lymphatic system. The presence of lymph node metastases is merely a reflection of the biological aggressiveness of the tumor, and systemic therapy is the foundation of treatment. There is no presumption that all the microscopic disease can or should be removed with surgery, even with an en bloc resection, as circulating tumor cells are already in the bloodstream by that point. Accordingly, the primary benefit of performing a more extensive lymphadenectomy in this setting is to sample an adequate number of 480

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lymph nodes so that understaging does not occur. This has led to widespread efforts to identify the minimum number of resected lymph nodes necessary to statistically confirm that the cancer is node negative by standard histologic methods. The argument that removing more lymph nodes results in better outcome is explained by the notion that the patients are better staged, and that N0 disease is truly N0. Acceptance of the more recent concept that a given tumor type represents a spectrum of biological behavior, leads to a rationale for lymphadenectomy with 2 purposes, both to stage the disease and importantly, to provide a potential therapeutic benefit. In a small tumor, early in its natural history, its biology may have allowed the ability to metastasize to nearby lymph nodes, but not as yet to distant organs. In this scenario, an extensive lymphadenectomy allows for removal of the entire tumor burden. In another, clinically similar tumor, its biology may have allowed systemic metastases with or without nodal involvement, and lymphadenectomy will not serve a significant therapeutic benefit. The presence of metastatic cells in the regional lymph nodes will be noted, but the presence of metastases to distant organs will be the governing factor of survival, often evident only years later. Unfortunately, the difficulty arises in knowing which scenario a given patient has. In fact, current clinical staging technology is too crude to differentiate these critically important different tumor biologies. As such, it can be argued that a reasonable approach is to assume that some portion of patients have locoregional disease and use a thorough lymphadenectomy with the expectation that it will be therapeutic. Under this approach, one recognizes that often the surgical pathology will reveal a greater disease burden than anticipated, and that the disease is likely systemic already, in which case the lymphadenectomy will have been done without therapeutic benefit. Hope rests on the ability of an improved understanding of genomics, tumor microenvironments, and perhaps tumor stem cell biologics to do so in the future. Relevant to these arguments is the potential morbidity of en bloc lymphadenectomy, which has historically been a component of the controversy. Recent data for most GI solid tumor types suggest lymphadenectomy can be added without significant increase in overall morbidity and mortality. Several studies have evaluated the mortality and morbidity of simple vs extended esophagectomy and have shown that they are similar (Table 1).10,14-21 Indeed, progressive improvements in intraoperative and postoperative care have largely eliminated mortality and morbidity as a factor in the selection of patients for 1 procedure vs another. Curr Probl Surg, August 2012

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TABLE 1. Mortality and morbidity as reported in the literature for transthoracic en bloc esophagectomy and transhiatal esophagectomy

Author and reference EBE Putnam and colleagues15* Horstmann and colleagues16* Altorki and colleagues17* Hulscher and colleagues18* Swanson and colleagues14 Hagen and colleagues10 Range THE Putnam and colleagues15* Horstmann and colleagues16* Altorki and colleagues17* Hulscher and colleagues18* Orringer and colleagues20 Rentz and colleagues21 Range

N

Mortality

Morbidity

LOS

134 41 78 114 250 100

8% 10% 5.1% 4% 3.6% 6% 3.6%-10%

75% ns 24% 57% 33% 71% 24%-75%

20 d 23 d ns 19 d 13 d 14 d 13-23 d

42 46 50 106 417 385

5% 11% 6% 2% 5% 9.9% 2%-11%

69% ns 26% 27% 32% 49% 26%-69%

19 d 26 d ns 15 d 11-14 d ns 11-26 d

*Both EBE (en bloc esophagectomy) and THE (transhiatal esophagectomy) are included in the study. Reprinted with permission from Johansson and colleagues.43

Patient Selection for Extended Lymphadenectomy Given the rationale outlined earlier in the text, it follows that en bloc esophageal and gastric resections, including 2- to 3-field lymphadenectomy, should not be routinely applied to all patients with GI solid tumors. Rather, treatment should be individualized, with lymphadenectomy focused on patients most likely to benefit, namely, those with regional disease. Given the inaccuracies of current clinical methods to distinguish these groups preoperatively, a liberal approach to the selection of patients for en bloc resection is necessary to maximize those who will benefit. Although by no means perfect, patients with a high likelihood of local, regional, and systemic disease can be approximated clinically as outlined for esophageal resection later in the text (Table 2). Similar concepts have been allied to patient selection in gastric cancer. Despite attempts at careful patient selection, it should again be noted that currently available clinical staging will result in some patients with either purely local or ultimately systemic disease undergoing a nontherapeutic lymphadenectomy. The clinician thus takes an approach favoring overtreatment rather than undertreatment, given the clinical safety of surgical lymphadenectomy. Identification of Local Esophageal Cancer. Local disease refers to cancers that are confined to the esophageal mucosa or submucosa without 482

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TABLE 2. Clinical phenotypes of disease in esophageal cancer Local disease (15%) Asymptomatic No visible lesion Endoscopic mucosal resection staging limited to mucosa (m1-3) Regional disease (25%) Minimal symptoms (anemia, surveillance) Small ⬍2-3 cm noncircumferential tumors Systemic disease (60%) Dysphagia ⬎3 cm circumferential tumor High number of positive nodes on endoscopic ultrasonography evaluation

nodal metastases. It is best characterized clinically as patients who are asymptomatic at presentation with no visible lesion on endoscopy. Studies have shown that the presence or absence of an endoscopically visible lesion in patients with biopsy proven high-grade dysplasia or intramucosal carcinoma is a predictor of tumor depth and nodal metastases. The data indicate that the absence of an endoscopically visible lesion almost always corresponds to an intramucosal tumor without nodal metastases. Nigro and colleagues, reviewing early-stage esophageal cancer, reported that when there was no visible lesion on endoscopy, 88% of the tumors were intramucosal and 12% were submucosal.22 Only 1 of 10 patients with no visible lesion had lymph node involvement either histologically or immunohistochemically. In contrast, patients with endoscopically visible tumors had a high prevalence of tumors that penetrated beyond the mucosa (75%), and 56% had positive nodes. Endoscopic ultrasonography has not been a reliable technique in distinguishing mucosal vs submucosal invasion, and endoscopic mucosal resection has been advocated as a superior staging technique for determining the true depth of invasion in these cases. Identification of Regional Esophageal Cancer. Patients with regional disease are best characterized by minimal symptoms and small (⬍2-3 cm) noncircumferential lesions on endoscopic examination (Fig 6). In the presence of these small visible lesions, the possibility of a submucosal tumor is high, but the likelihood of cure is also significant. As the depth of tumor increases, the likelihood of nodal involvement increases.23,24 Although tumors that invade through the muscularis mucosa into the submucosa have a 60% or more incidence of lymph node metastasis, more than half have fewer than 4 positive lymph nodes, a situation that remains curable. As such, some have advocated the performance of a lymphadenectomy with esophagectomy in the treatment of visible lesions. Curr Probl Surg, August 2012

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FIG 6. Endoscopic view of a noncircumferential adenocarcinoma of the lower esophagus representing regional disease. (Color version of figure is available online.)

Alternatively, endoscopic mucosal resection is an excellent technique to determine the true depth of invasion of these lesions, as visible lesions with truly mucosal depth of invasion can still be treated with esophageal preservation. Identification of Systemic Esophageal Cancer. Patients with more advanced disease usually present with dysphagia and a greater than 3-cm circumferential lesion on endoscopy. These tumors are associated with extensive lymph node involvement, which is obvious with endoscopic ultrasonography evaluation, and are unlikely to be cured. The presence of more advanced disease in patients who suffer from dysphagia is reflected in the poor survival seen in these patients compared with patients who present with either nonspecific or no symptoms (Fig 7). In this circumstance, a palliative operation seems justified. Some would argue to palliate symptoms with chemoradiation therapy. Transhiatal esophagectomy, however, has been shown to be more effective in relieving dysphagia than nonsurgical treatment.

Studies of the Extent and Distribution of Metastatic Lymph Nodes and Recurrence Patterns The probability of any positive metastatic lymph node, the relative proportions of multiple positive lymph nodes, and the distribution of positive lymph nodes have been well studied in both esophageal and 484

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FIG 7. Overall survival of patients presenting with dysphagia as compared with other symptoms. (Reprinted with permission from Williams and colleagues.9)

gastric cancer over the past 20 to 30 years. In general, the prevalence of node metastasis is dependent on several factors including the following: (1) the depth of penetration of the tumor (Fig 8), (2) the location of the tumor, and, to a lesser extent in esophageal cancer (3) the histologic type of the tumor.

Esophageal Cancer Lymphatic metastasis in esophageal cancer has been well documented to have significant variability. This is largely because of the extensive lymphatic channels within the esophageal wall. Lymphatic channels begin in the lamina propria and coalesce into an extensive lymphatic network in the submucosal layer. These anatomic characteristics allow metastatic cells to travel significant distances along the longitudinal esophageal axis before draining into regional mediastinal lymph nodes. Contrast studies of submucosal lymphatics have calculated a longitudinal lymph flow of as much as 6 times the transverse flow.26 This results in the capacity to form metastatic lymph nodes well away from the location of the primary tumor. As such, the segmental lymphatic drainage of the esophagus is much less predictable than, for example, the colon. The drainage pattern of esophageal lymphatics is determined in part by the tumor’s location in relationship to the carina. Tumors superior to the carina preferentially drain cephalad toward the upper mediastinum and neck, whereas tumors inferior to the carina drain into the lower mediastinum and upper abdomen. This is because of the presence of valves in the lymphatic vessels.27 The lymphatic drainage of the distal esophagus is in continuity with the lymphatics of the proximal stomach. It is also Curr Probl Surg, August 2012

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FIG 8. Prevalence and location of metastatic lymph node involvement based on depth of penetration of esophageal adenocarcinoma. (Reprinted with permission from Feith and colleagues.25)

important to note that occlusion of lymphatic channels by tumor cells may result in reversal of flow or drainage via alternate pathways. Thus, metastatic lymph nodes in patients with esophageal cancer can occur in the neck, mediastinum, or abdomen, regardless of where the tumor resides. 486

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FIG 9. Graphic representation of the average prevalence and number of positive lymph nodes, percent of nodes in distant nodal basins, celiac node positivity, and 5-year survival based on depth of tumor presentation. Values are an average representation of literature reports.

In general, a relatively orderly progression of lymph node metastases is observed when analyzed by the depth of tumor penetration (Fig 9).25 Increasing depth of tumor penetration results in increasing nodal metastases in the peritumoral regional node stations followed by metastases to more distant lymph nodes as the tumor becomes more invasive. On average, approximately 50% to 60% of patients with surgically resectable esophageal cancer will have developed lymph node metastases at the time of presentation. Importantly, however, many node-positive patients will have a small nodal burden (⬍4-8), a circumstance in which regional lymphadenectomy may still provide a cure (Fig 10). High numbers (⬎8-10) of positive nodes, or alternatively a high percentage of positive nodes (⬎50%), often indicate systemic disease and preclude curability despite lymphadenectomy. Skip metastases are also common in foregut malignancies, and particularly in esophageal cancer. Skip metastases to nodal stations distant from the primary tumor have been reported in up to 34% of patients when assessed using routine hematoxylin and eosin staining, and up to 70% when assessed using immunohistochemistry.28 This inherent unpredictability of the pattern of nodal metastases has led some surgeons to advocate routine lymphadenectomy that includes lymph Curr Probl Surg, August 2012

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FIG 10. Relationship of tumor depth with number and prevalence of nodal metastasis in patients with esophageal cancer.

nodes from all 3 compartments (neck, chest, and abdomen, see later in the text).23,29 The clinical significance of lymph node metastases in the neck and the benefit of cervical lymphadenectomy has been the most controversial of the 3 compartments. Data reported from Japan in patients with squamous cell carcinoma and a high prevalence of middle and upper third tumors indicate an overall prevalence of cervical nodal metastases of 30% to 50%. The prevalence is dependent on the location of the primary tumor.30,31 On average, cervical node metastases occur in 60% of upper third, 20% of middle third, and 12% of lower third squamous cell carcinomas.30,32 Similar data have been reported in Western surgical series, although most find a lower rate of cervical node metastases. The overall prevalence of cervical lymph node metastases averages 20% to 40% in Western series.33-35 At first glance, this might be assumed to be because of the higher prevalence of distal adenocarcinoma in the West; however, when analyzed by histological subtype, there was no significant difference.33,34 The majority of lymph node metastases in mid-esophageal tumors will occur in the mediastinal lymph node compartment. Most mid-esophageal tumors are squamous cell carcinomas, and these tumors represent 70% of the esophageal cancers reported in Japan.36 Lymph node metastases in lower esophageal tumors commonly occur both in the mediastinum and upper abdomen, occurring on average in 10% to 40% of patients.23,24,30,37,38 The lower mediastinal lymph node stations are commonly involved, and the prevalence of metastatic nodes in this location is second only to lesser curvature nodes. On average, 52% of nodes in the 488

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lower mediastinum will prove histologically positive.37 Both mediastinal and abdominal compartments are commonly positive. Lower esophageal cancers are found to harbor both lower mediastinal and abdominal nodal metastases in 77% of lymph node-positive patients, isolated abdominal metastases in 18%, and isolated mediastinal metastases in 8%.39 Subcarinal nodal metastases are not as frequent as lower mediastinal metastases (half), although when positive usually precludes cure in distal esophageal cancers.37 As a general observation, subcarinal and/or upper mediastinal lymph node metastases increase in the setting of significant numbers of abdominal and regional positive lymph nodes. Given 1 to 3 positive lymph nodes in the lower mediastinum, paracardial region, or lesser curvature, 5% to 6% of patients will have positive upper mediastinal or subcarinal lymph nodes.25 In contrast, when more than 6 regional nodes are involved, as many as 40% of patients will have upper mediastinal or subcarinal nodal involvement. The depth of tumor invasion is also a significant factor influencing the rate of metastases to the subcarinal nodal station. When tumors are limited to the submucosa, subcarinal metastases are relatively uncommon, occurring in approximately 8% of patients. In comparison, tumors invading the muscularis propria have a 20% prevalence of positive subcarinal lymph nodes.23 Lymph node metastases in the upper abdominal compartment are common in esophageal cancer, regardless of tumor histology. Although one would assume that proximal squamous cell carcinomas would have a low prevalence of nodal metastases to the abdomen, this is not the case, with reports of positive lymph nodes in more than 50% of such patients.31 Distal third adenocarcinomas and those of the gastroesophageal junction have a similar prevalence of abdominal node metastases.35 Hulscher and colleagues have analyzed the location of abdominal node metastases with the highest prevalence in the lesser curvature station (64% of nodepositive patients), followed by left gastric artery nodes (47%) and hepatic/splenic artery/celiac axis (28%).37 A unique group of patients is those with solitary nodal metastases. Analysis of the pattern of lymph node metastases in specimens after esophagectomy with 3-field lymphadenectomy has demonstrated that nearly all occur in the upper abdominal or lower mediastinal lymph nodes. The most common locations are right and left paracardial lymph nodes (29.0% and 26.4%, respectively) and lower posterior mediastinum (24%). No significant difference between the 2 compartments has been identified (Fig 11).25 These observations emphasize the importance of adding the mediastinal field to the esophageal resection to maximize the chances of removing all involved lymph nodes. Curr Probl Surg, August 2012

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FIG 11. Prevalence and location of lymph node metastases in 42 patients with esophageal adenocarcinoma and single node metastases. (Reprinted with permission from Feith and colleagues.25)

In summary, general patterns are well known in the pattern of lymph node metastasis in esophageal cancer, although it can be unpredictable due to the lymphatic anatomy and the ability of lymphatic flow to course to and from the neck, mediastinum, and abdomen. Approximately one half of surgically resectable patients will be found to be node positive with the prevalence and distribution based on the depth of penetration and location of the tumor. It is uncommon for metastases to occur in only 1 of the 3 compartments; however, when it occurs, metastases to the upper abdominal nodes are equally as frequent as metastases to nodes of the lower mediastinum. Cervical lymph node metastases occur in a small, but significant, proportion of patients, including those with tumors of the lower esophagus. The prevalence and pattern of nodal metastasis in patients with adenocarcinoma and squamous cell esophageal carcinoma are similar when adjusted for the location of tumor.

Gastric Cancer Although the intramural lymphatic anatomy of the stomach is similar to the esophagus with extensive submucosal lymphatic channels that allow for spread of metastatic cells away from the primary tumor, the nodal 490

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spread of gastric cancer is typically limited to the abdominal lymph node compartment. The lymphatic system in the upper abdomen mirrors the vasculature anatomy of the stomach. Skip metastases have also been commonly noted in gastric cancer, occurring in up to 30% of patients.40 Japanese researchers have established a comprehensive understanding of the pattern of lymph node metastases in gastric cancer. The pattern is dependent on the location of the tumor and is currently incorporated into the Japanese gastric cancer staging classification including both N and M stage. This is distinct from Western TNM systems, whereby the number of lymph nodes determines the N status rather than the location. Typical metastatic patterns for upper third, middle third, and lower third tumors have been well described. In general, tumors spread into the perigastric lymph nodes near the respective portion of the stomach, then proceed into the gastric vascular region, and finally into the periaortic region. The most common locations for nodal metastases for all tumor locations are the lesser curvature lymph nodes (29%), followed by infra-pyloric (23%), greater curvature (22%), right cardia (19%), and left gastric artery (19%) nodal stations.41 When nodal metastasis prevalence is broken down by tumor location, there are some differences.41 Upper third tumors metastasize most frequently to the lesser curvature lymph nodes (33%), right cardia lymph nodes (31%), and left gastric artery lymph nodes (19%). Middle third tumors metastasize most commonly to the lesser curvature lymph nodes (40%), greater curvature lymph nodes (31%), and left gastric artery lymph nodes (22%). Distal third tumors most frequently spread to the infra-pyloric lymph nodes (49%), lesser curvature lymph nodes (38%), and greater curvature lymph nodes (35%). The Japanese staging system considers metastases to select lymph node stations as systemic disease.42 The node station considered M disease varies based on the location of the tumor. For example, a short gastric vessel lymph node metastasis for a lower third tumor is M1, but N1 for an upper third tumor. Some lymph node stations are considered systemic disease when involved regardless of the location of the primary tumor. These include nodes near the superior mesenteric and middle colic arteries, aortic hiatus, lower periesophageal, supradiaphragmatic, and posterior mediastinal nodes. This M1 designation is thought to reflect the natural history of spread in gastric cancer. Essentially, early metastases start in the perigastric lymph nodes, enter the left gastric and celiac vasculature bed, and then extend into the para-aortic, hepatic, duodenal, pancreatic, and splenic regions. FiCurr Probl Surg, August 2012

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TABLE 3. Reported ability of transthoracic en bloc esophagectomy and transhiatal esophagectomy to control local regional disease Author and reference EBE Matsubara and colleagues32 Altorki and colleagues44 Hagen and colleagues10 Collard and colleagues45 Swanson and colleagues14 Range THE Hulscher and colleagues46 Becker and colleagues47 Gignoux and colleagues48 Nygaard and colleagues49 Range

Number of subjects

Local recurrence (%)

171 111 100 324 250

10 8 1 4 5.6 1-10

137 35 56 186

23 31 47 35 23-47

Reprinted with permission from Johansson and colleagues.43

nally, nodal spread into the mediastinum or retroperitoneum indicates distant or systemic metastases.

Patterns of Recurrence Analysis of the patterns of neoplastic recurrence also provides useful information to guide concepts of the extent of initial resection. Esophageal and gastric cancer may recur locally within the field of previous resection, regionally within distant lymph nodes outside the field of dissection, or systemically. Both esophageal and gastric cancers have a high (up to 40% to 50%) rate of local recurrence, but this differs based on extent of resection. The high rate of local recurrence after simple dissection and the relatively low rate of local recurrence after en bloc resection provide further rationale for an extended lymphadenectomy. Several studies have shown the local recurrence rates after transhiatal esophagectomy to be in the range of 23% to 47% (Table 3).46-49 In contrast, local recurrence rates after en bloc esophagectomy have been reported to be as low as 1% to 10%.14,32,44,45 Clark and colleagues reported that virtually all tumor recurrences in patients after en bloc resection were either distant (nodes outside the field of dissection) or systemic.24 Thus, excellent local control was established. It has been shown that after esophagectomy with extended lymphadenectomy, the likelihood of tumor recurrence increases with tumor depth and the number of metastatic lymph nodes within the surgical specimen.11 This trend is not seen in patients who have received a transhiatal esophagectomy, and is related to the fact that transhiatal esophagec492

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TABLE 4. Combined-modality therapy for esophageal cancer: patterns of failure High dose (64.8 Gy) (n ⴝ 109)

Alive/no failure Any failure Persistent local disease Local failure Regional failure Distant failure Regional and distant failure Total local/regional persistence/failure Treatment-related death Second primary cancer Cancer death/or not specified Dead of intercurrent disease

Standard dose (50.4 Gy) (n ⴝ 109)

No.

%

No.

%

21 88 36 10 8 10 0 54 11 4 3 6

19 81 33 9 7 9 0 50 10 4 3 6

27 82 37 13 8 17 2 60 2 1 0 2

25 75 34 12 7 16 2 55 2 1 0 2

Reprinted with permission from Minsky and colleagues.50

TABLE 5. Anatomic fields of lymph node dissection in esophageal cancer Field

Location (Nodal dissection)

1 2 3

Abdominal (parahiatal, lesser curve, left gastric, splenic, hepatic) Lower mediastinal (thoracic duct, paraesophageal, subcarinal) Cervical and upper thoracic (left and right recurrent nerve chains, lateral and posterior internal jugular, supraclavicular)

tomy by nature removes significantly fewer lymph nodes in the surgical specimen and therefore does not allow an accurate assessment of nodal staging. Some would propose removal of the primary tumor followed by the use of radiation to control local disease. However, the ability of radiation therapy to control local disease has not been shown conclusively (Table 4).

Technique of En Bloc Resection with Extended Lymphadenectomy Esophageal Cancer Two- or 3-field lymph node dissection is carried out based on the location of the tumor and surgeon preference.51,52 This includes lymphatic compartments in the chest, abdomen, and/or the neck (Table 5). Two-field lymphadenectomy includes dissection of the chest, including the thoracic duct, subcarinal nodes, and periesophageal mediastinal Curr Probl Surg, August 2012

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lymph nodes. For middle and upper third tumors, the lymph nodes along the recurrent laryngeal nerves in the upper mediastinum are also dissected. The abdominal component is a D2 nodal dissection. The 3-field lymphadenectomy includes the identical dissection of the abdominal and thoracic compartments but also removes the cervical nodes bilaterally, including the deep internal, external, and lateral cervical of the neck.51,52 A modified limited 2-field approach, suitable for early-stage tumors (T1b, T2), has been advocated by some authorities.51,52 This includes a transhiatal resection of the distal posterior mediastinal nodal stations and the abdominal lymph node compartment. Sentinel Lymph Node Assessment in Esophageal Cancer. The sentinel lymph node (SLN) is defined as the first lymph node that receives lymphatic drainage from the primary tumor and is theoretically the first potential site of micrometastasis along the course of lymphatic drainage from the primary tumor.53,54 The concept of sentinel node biopsy has been successfully applied to melanoma and breast cancer and rests on the fact that if the sentinel node (or occasionally 2 to 3 nodes) are negative, further lymph node metastases are highly unlikely and lymphadenectomy is unnecessary.53,54 However, as mentioned earlier in the text, esophageal cancer is characterized by multidirectional lymphatic drainage and variable patterns of lymph node metastases, which may include cervical, mediastinal, or abdominal compartments often with skip metastases.28 As such, sentinel node mapping for esophageal cancer is relatively complicated. Despite this fact, recent studies suggest that the SLN concept may be feasible, particularly in patients with early-stage esophageal cancer. Successful use allows an individualized surgical approach to lymphadenectomy.55-57 Takeuchi and colleagues have reported its use in 75 patients with clinical T1N0M0 or T2N0M0 tumors, concluding that radio-guided SLN mapping is an accurate procedure for detecting lymph node metastasis in patients with early-stage esophageal cancer, and the diagnostic accuracy based on SLN status was 94%.56 Others have come to similar conclusions and have also advocated its use.58 Future multicenter clinical trials using standardized protocols are required to determine whether SLN mapping in esophageal cancer is suitable for clinical practice. Technique of En Bloc Esophagectomy. Although bilateral paratracheal lymphadenectomy is possible for tumors of the middle and upper third esophagus, the technique of en bloc esophagectomy will be described for resection of carcinoma of the distal esophagus and cardia. In brief, it is performed through 3 incisions. The procedure begins with a right posterolateral thoracotomy proceeding to en bloc dissection of the 494

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esophagus below the aortic arch. The esophagus above the aortic arch is dissected without regard to extensive lymphadenectomy; obvious enlarged nodes are removed. The chest incision is then closed, and the patient is repositioned supine. An upper midline abdominal incision is then made, and en bloc dissection of the stomach and associated lymph nodes takes place. Finally, a left neck incision is made, and the esophagus is divided proximally. The specimen is then removed through the abdomen, and a gastric tube is formed with attention to ample resection of the lesser curvature nodal stations. Reestablishment of GI continuity can be performed with either a gastric pull-up or colon interposition. The thoracic portion of the resection includes en bloc dissection of the esophagus below the aortic arch, with its surrounding areolar tissue containing the low paratracheal, tracheobronchial, subcarinal, paraesophageal, and parahiatal lymph nodes. The resection includes the azygos venous system and thoracic duct, both taken to the level of aortic hiatus of the right diaphragm. The esophagus is typically not seen during this dissection in an effort to preserve this mediastinal block of tissue. A collar of diaphragmatic muscle around the esophageal hiatus is also included. The en bloc dissection field is limited anteriorly by the pericardium and membranous wall of the trachea and posteriorly by the intercostal arteries, aorta, and anterior vertebral ligament. A strip of pleura from both the right and left pleura marks the lateral borders of the dissection. The abdominal portion of the resection includes en bloc removal of the posterior peritoneal and periaortic areolar tissue to the level of the celiac axis and the borders of the common hepatic and splenic arteries similar to a D2 resection for gastric cancer. The block of tissue includes lymph nodes along the left gastric artery, the celiac axis, superior and posterior to the common hepatic artery, medial to the portal triad, and if necessary along the splenic artery to the celiac axis. This extensive resection is done to incorporate into the surgical specimen all the potentially involved regional lymph nodes and submucosal lymphatics of the stomach and distal esophagus. The pancreas and spleen are not removed. Details of the Procedure. The procedure begins with a right posterolateral thoracotomy through the sixth or seventh intercostal space along the upper border of the seventh or eighth rib. This allows excellent exposure to the lower mediastinum for the nodal dissection. The dissection plane begins lateral to the azygos system with dissection and division of each intercostal branch of the azygos from its arch to where it passes into the abdomen on the lateral surface of the vertebra. This is accomplished by opening the posterior pleura over the intercostal veins with an incision parallel to the long axis of the spine. The posterior dissection is Curr Probl Surg, August 2012

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FIG 12. Intraoperative photograph of the skeletonized aorta after transthoracic en bloc esophagectomy. (Color version of figure is available online.)

extended in the direction of the left chest, skeletonizing each intercostal artery as it inserts into the aorta. All lymph node bearing tissue is swept up with the specimen, laying bare the anterior surface of the aorta, through the left mediastinal pleura, and into the left pleural cavity (Fig 12). This dissection requires the intact azygos vein and its surrounding tissues to be retracted anteriorly by the assistant, which allows the hemiazygos veins to be seen as they cross over the spine beneath the aorta to join the azygos system. These hemiazygos veins must be identified, ligated, and divided. Early division of the azygos vein at its junction with the superior vena cava is avoided because it contributes to venous hypertension in the azygos system and may increase bleeding during the posterior mediastinal dissection. At the caudal end of the posterior pleural incision, where the azygos vein is ligated distally, the thoracic duct is carefully identified, divided, and specifically ligated. Anteriorly, the pleura is incised along the inferior border of the inferior vena cava and extended cephalad along the posterior margin of the pericardium to the level of the tracheal bifurcation and caudally to the level of the right crus. The anterior dissection is extended across the midline in the direction of the left chest along the posterior surface of the right main stem bronchus, trachea, left main stem bronchus, and the pericardium anterior to the subcarinal lymph nodes. To do so requires division of the azygos vein at its entry into the superior vena cava. When 496

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FIG 13. Intraoperative photograph of competed lower mediastinal en bloc dissection encompassing the esophagus and its mesentery, azygos venous system, thoracic duct, and all lymph node-bearing tissue. (Color version of figure is available online.)

both the anterior and posterior dissections of the posterior mediastinum are complete, the esophagus, encased in its periareolar tissues containing the paratracheal, subcarinal, paraesophageal, and parahiatal lymph nodes, is pulled into the right thorax and freed by sharp division of a strip of left mediastinal pleura (Fig 13). Care must be taken to avoid damage to the left recurrent laryngeal nerve near the aortic arch. This nerve can be identified as it passes underneath the aortic arch just above the left mainstem bronchus. Its common course is to pass directly toward the trachea without redundancy and to lie on the left posterolateral cartilaginous wall as it passes up into the neck. Identifying it underneath the aortic arch allows for mobilization of the proximal esophagus without damage to the nerve. Inferiorly, a collar of diaphragmatic muscle is excised around the esophageal hiatus. Superiorly, the esophagus above the carina is bluntly dissected into the neck but is not divided. No attempt is made to do an en bloc dissection above the level of the aortic arch and the dissection plane remains on the esophagus to prevent injury to the right recurrent laryngeal nerve. Suspicious lymph nodes above the aortic arch are removed when identified. Hemostasis is ensured, and with the specimen remaining in the chest, the thoracotomy incision is closed. Next, the patient is repositioned supine as for a transhiatal esophagectomy. The previously inserted double-lumen endotracheal tube, Curr Probl Surg, August 2012

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used for selective deflation of the right lung, is removed and a single-lumen tube is inserted. The anterior left neck, chest, and abdomen are prepared and draped, and an upper midline abdominal incision is made. Exposure for the abdominal dissection is facilitated by a Weinberg retractor, which has been welded to a Balfour handle and attached to an over-arm bar. The abdominal dissection begins with mobilization of the greater curve of the stomach in preparation for gastric pull-up. The gastrocolic omentum is opened into the lesser sac along the mid portion of the greater curvature and bridging veins ligated proximally and distally. The dissection is taken into the splenic hilum where the short gastric vessels are divided using a harmonic scalpel. The abdominal dissection continues along the left crus, to meet the thoracic dissection. The excision of a collar of diaphragmatic muscle is continued along the margin of the left crus to the celiac axis. The left gastric artery and celiac axis are skeletonized from the left, and all retroperitoneal periaortic areolar tissue superior to it is removed with the specimen. On the right side, the gastrohepatic ligament is divided along the liver margin up to the esophageal hiatus. Care must be taken not to interrupt a large aberrant hepatic artery that might be lying in this mesentery. If present, it can be either divided or carefully dissected and skeletonized back to its junction with the left gastric artery. The posterior peritoneal tissue underneath and along the superior border of the common hepatic artery, and the areolar tissue containing lymph nodes along the medial border of the portal triad, is swept toward the celiac axis. Dissection of a collar of diaphragmatic muscle around the esophageal hiatus, which was begun during the thoracic portion of the operation, is continued down the right crus. The dissection of the hiatus is completed with the division of the left gastric artery at its origin from the celiac artery or just distal to a large aberrant hepatic branch. The esophagus is exposed and divided in the left neck through an incision made along the anterior border of the sternocleidomastoid muscle. Care is taken to identify and protect the left recurrent laryngeal nerve. The cervical esophagus is divided, leaving a length of 3 to 4 cm, and the specimen is removed from the posterior mediastinum transabdominally. A proximal one third to one half vertical gastrectomy is carried out using a 75-mm GIA stapler, creating a gastric tube. A 5- to 10-cm margin is necessary from the tumor and can usually be accomplished. GI continuity is reestablished between the proximal esophagus in the neck via gastric pull-up, or when more extensive gastric involvement is present, via sparing of the gastric antrum and reconstruction using an 498

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FIG 14. Lymph node stations in gastric cancer classified according to the Japanese Gastric Cancer Association. (Reprinted with kind permission from Springer Science ⫹ Business Media from Siewert JR, Rothmund M, Schumpelick V. Praxis der viszeralchirurgie. Onkologische Chirurgie 2010;3:541.) (Color version of figure is available online.)

isoperistaltic left colon transplant based on the left colic artery and the inferior mesenteric vein. A feeding jejunostomy tube is routinely inserted and the abdominal and neck incisions closed.

Gastric Cancer The Japanese Gastric Cancer Association differentiates 16 unique lymph node stations surrounding the stomach.59 These are classified into the following 3 groups, D1 to D3 (Fig 14): D1: perigastric lymph nodes (stations 1-6); D2: lymph nodes along the left gastric (station 7), common hepatic (station 8), splenic (station 11), and proper hepatic (station 12) arteries, and along the celiac axis (station 9); D3: pari-aortic lymph nodes (station 16). A D1 lymphadenectomy is defined as a simple resection and includes only the perigastric lymph nodes adjacent to the stomach.61 D2 lymphCurr Probl Surg, August 2012

499

adenectomy is the primary procedure of choice and includes perigastric as well as lymph nodes of the D2 compartment outlined above. Finally, a D3 lymphadenectomy also includes the pari-aortic lymph nodes.61 For better lymph node clearance during D2 lymphadenectomy, resection of the spleen or the pancreas or both might be an option, which is discussed below in more detail.61 Sentinel Lymph Node Assessment in Gastric Cancer. Although the concept of SLN assessment has also been evaluated for gastric cancer, to date no standardized approach has been established. Tumors can be injected pre- or intraoperatively, in the submucosa or subserosa, and tracers including 1% isosulfan blue or technetium-99m Sn colloid are described with identification either by direct visualization or gamma probe.62-66 Recent studies report an average detection rate of 1 to 4 SLN with encouraging sensitivity, specificity, and accuracy but a negative predictive value of only 50%.62-66 Tumor stage seems to highly influence the feasibility of the SLN assessment in gastric cancer. In fact, advanced tumors are generally excluded because the chance of a false-negative SLN is high. This is likely because advanced cancer obstructs the lymphatic vessels, causing the tracer to flow to negative lymph nodes.66 In contrast, evidence is accumulating to suggest that SLN assessment may be useful in patients with early gastric cancer allowing a selection of node negative patients for less extensive lymphadenectomy.67,68 Despite recent promising data in patients with early stage tumors, the technique is not widely practiced largely due to nonstandardized examination protocols and limited data to date.69,70

Outcome Data Supporting Extended Lymphadenectomy Esophageal Cancer The performance of en bloc esophagectomy is not common but occurs in centers around the world, including select centers in the United States, United Kingdom, Germany, Belgium, and Japan. Studies to date encompass retrospective case series, case– control studies, population-based studies, and a prospective randomized trial. Hagen and colleagues reported a retrospective review of the University of Southern California experience of 100 consecutive patients who underwent en bloc esophagectomy and 2-field lymphadenectomy for esophageal adenocarcinoma.10 No patient received pre- or postoperative radiation or chemotherapy. The median follow-up was 40 months, and 23 patients had survived more than 5 years. Overall actuarial survival at 5 500

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FIG 15. Actuarial survival including operative mortality for 100 consecutive patients undergoing en bloc esophagectomy for cure of esophageal carcinoma. (Reprinted with permission from Hagen and colleagues.10)

years was 52% (Fig 15). Fifty-five of the tumors were transmural, and 63 patients had lymph node involvement. Metastases to celiac (n ⫽ 16) or other distant node sites (n ⫽ 26) were not associated with decreased survival. Remarkably, local recurrence within the field of dissection was seen in only 1 patient. Nodal recurrence outside the surgical field occurred in 9, and systemic metastases occurred in 31 patients. One third of patients with lymph node involvement survived 5 years, and local control was excellent after en bloc resection. This evidence strongly suggests that transthoracic en bloc resection results in better control of local-regional disease (Table 3). Altorki and Skinner, reporting the experience at Cornell University, have suggested that en bloc esophagectomy should perhaps be the standard of care.44 They reported the outcome of esophagectomy with en bloc lymphadenectomy in 111 largely unselected patients, nearly all of whom did not receive neoadjuvant therapy. Five-year survival was 40%, among the best reported at the time of publication. More than 50% of the patients had stage III or IVa, and 60% were node positive. Johansson and colleagues reported a retrospective comparison of transthoracic en bloc resections and transhiatal simple resections in a case– control series of patients from the University of Southern California with transmural (T3) esophageal adenocarcinomas with 8 or fewer lymph nodes involved (N1).43 The aim was to compare survival in similar patients with pathologic T3N1 disease (Fig 16). The approach could remove the influence of inaccurate preoperative staging and minimize the influence of postoperative stage migration on survival since all patients had N1 disease. The authors required that more than 20 lymph nodes were Curr Probl Surg, August 2012

501

FIG 16. Survival of T3N1 patients with 1 to 8 metastatic lymph nodes who had a transthoracic en bloc lymph node dissection (n ⫽ 18) and those who had a transhiatal lymph node dissection (n ⫽ 13). Log rank test, statistic 10.25, d.f. ⫽ 1, P ⫽ 0.0006. (Reprinted with permission from Johansson and colleagues.43)

in the surgical specimen to provide confirmation that the extent of lymph node disease in both groups was comparable. As much as possible, the study conditions focused the question on which procedure was associated with a better survival. Analysis identified only 2 independent factors that affected survival in the studied population: the type of resection and extent of lymph node disease categorized according to the number of involved nodes. Other attempts have been made to determine whether the extent of resection affects survival (Table 6). Four of these studies were retrospective, and none made an attempt to limit the studied population to T3N1 disease. Although statistically significant in 3 of the 4 reports, their conclusions support but do not provide definitive evidence of the benefit of extended lymphadenectomy. In a population-based retrospective case– control study comparing survival after transhiatal and transthoracic en bloc resection in Finland, Sihvo and colleagues compared the outcomes of 42 patients following esophagectomy with 2-field lymphadenectomy to 129 patients after 502

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TABLE 6. Comparison trials between transhiatal esophagectomy (THE) and transthoracic en bloc esophagectomy (EBE) on long-term survival Type of trial

n

THE

EBE

Putnam and colleagues15

Author and reference

Retro

12% (4 yr)

30% (4 yr)

0.02

Horstmann and colleagues16

Retro

18% (3 yr)

17% (3 yr)

NS

Altorki and colleagues17

Retro

11% (4 yr)

35% (4 yr)

0.007

Hulscher and colleagues18

RCT

102 EBE 30 THE 41 EBE 46 THE 78 EBE 50 THE 114 EBE 106 THE

P-value

27% (5 yr)

39% (5 yr)

0.08

Retro, retrospective clinical study; RCT, randomized controlled study. Reprinted with permission from Johansson and colleagues.43

FIG 17. Five-year survival of patients after esophagectomy with 2-field lymphadenectomy vs standard esophagectomy. Log rank test, P ⫽ 0.005. (Reprinted with permission from Macmillan Publishers Ltd from Sihvo and colleagues.19)

standard esophagectomy.19 Slightly less than half (42%) of all cancers of the esophagogastric junction underwent resection. Five-year survival was significantly better in patients with 2-field lymphadenectomy (50%) than in those with less extensive resections (23.2%, P ⫽ 0.005) (Fig 17). Eight-year survival rates were also better (43% vs 21%), suggesting that the effect is long-lasting. The authors concluded that in centers with experience, “radical surgery” with extended lymphadenectomy should be favored for those patients eligible for major surgery. The only prospective randomized controlled study to date was performed in the Netherlands and reported by Hulscher and colleagues.18 This study randomly assigned 220 patients with adenocarcinoma of the middle/distal esophagus or gastroesophageal junction either to transhiatal (n ⫽ 106) or transthoracic en bloc (n ⫽ 114) esophagectomy with Curr Probl Surg, August 2012

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FIG 18. Overall survival of patients with esophageal adenocarcinoma after transhiatal (TH) or transthoracic (TT) en bloc esophagectomy. (Reprinted with permission from Hulsher and colleagues,18 ©2002 Massachusetts Medical Society.)

lymphadenectomy. The endpoints were overall survival and disease-free survival while perioperative morbidity and mortality were also determined. Perioperative morbidity was higher after the transthoracic approach without a significant difference in hospital-mortality. The study showed a trend (P ⫽ 0.08) toward better survival with the en bloc resection (Fig 18). Disease-free survival was 27% in the transhiatal and 39% in the en bloc group, whereas the overall survival rates were 29% and 39%, respectively. Unfortunately, the study was underpowered. Calculations for sample size were based on a survival of 30% after simple transhiatal dissection, whereas the literature would support a 25% survival rate at best. Furthermore, the investigators estimated a 15% difference between the procedures but actually observed a 10% difference. Given these data, the correct sample size required to detect a statistical difference would be 260 patients per arm, whereas they enrolled 110 patients per arm. An update of this trial with longer follow-up included a subgroup analysis in which survival differed depending on the number of positive lymph nodes in the surgical specimen.71 Patients with 1 to 8 positive lymph nodes showed a significant 5-year disease-free survival advantage for patients undergoing transthoracic en bloc esophagectomy. The benefit was lost in those with more than 8 positive lymph nodes, as well as in those without nodal disease. This is an important observation and provides further conceptual rationale of the importance of identifying regional vs systemic disease. Large numbers of positive nodes reflect a 504

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TABLE 7. Independent predictors of survival by Cox regression in 2303 patients with esophageal cancer

Rank

Factor

␹2

1 2 3 4 5 6 7

No. involved nodes* Tumor depth (T) No. nodes removed* Node status (N) Cell type Age Gender

614 195 65 41 28 20 9

P-value ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.0024

Reprinted with permission from Peyre and colleagues.76

high likelihood of systemic disease, a concept that has been largely proven in studies of patients with breast cancer. Conversely, the extent of resection does not matter for those patients who are N0. Unfortunately, current technology does not allow accurate determination of the numbers of metastatic nodes before surgical decisions. It does, however, underscore the principle that regional disease exists, that lymphadenectomy in this population has a therapeutic benefit, and that clinical phenotypes of regional disease should be more accurately developed. Taken together, these studies from around the world provide significant support that for a substantial subset of patients with both squamous and adenocarcinoma of the esophagus, en bloc esophagogastrectomy results in significantly better survival rates than current techniques lacking extended lymphadenectomy (transhiatal, Ivor Lewis, and minimally invasive esophagogastrectomy). This finding is unlikely to be because of bias in the stage of disease resected, difference in operative mortality, or death from nontumor causes. Rather, it appears to be due to the type of operation performed. Impact of the Number of Resected Lymph Nodes. Two large multinational studies have assessed the benefit of lymphadenectomy as measured by total number of surgically removed lymph nodes.72-77 Both strongly suggest that increased number of surgically resected nodes is independently associated with overall and disease-free survival in esophageal cancer.72-77 Peyre and colleagues reported an international study on the impact of extent of surgical resection in 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous cell carcinoma) undergoing primary R0 esophagectomy for cancer.76 The number of lymph nodes removed was an independent predictor of survival (Table 7). Further analysis suggested the optimal threshold to obtain a survival benefit was 23 lymph nodes (Fig 19). More recently, a Worldwide Esophageal Cancer Collaborative assessed the optimum lymphadenectomy in 4627 paCurr Probl Surg, August 2012

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FIG 19. Results of Cox regression modeling in 2303 patients with esophageal cancer using thresholds of lymph nodes removed, ranging from 1 to 60 nodes. (Reprinted with permission from Peyre and colleagues.76)

tients.77 A similar conclusion was made, with greater extent of lymphadenectomy as measured by the number of lymph nodes was associated with increased survival except at the extremes (T0, T1a, and T4 tumors). Survival was strongly associated with the number of lymph nodes removed even when controlling for the type of resection and T stage (Table 8). The data suggested that the optimal number of resected nodes was 10 for pT1, 20 for pT2, and 30 for pT3/T4 patients. An important observation from both of these large studies is that for maximal therapeutic benefit, 20 to 30 lymph nodes should routinely be removed, and the only esophageal resection technique that reliably accomplishes this is the transthoracic en bloc esophagectomy. The benefit of removing more lymph nodes is postulated to be secondary to the removal of subclinical micrometastatic disease. 3-Field vs 2-Field Lymphadenectomy. Because of the observation of high neck recurrence rates in patients with esophageal squamous cell cancer, esophagectomy with 3-field lymphadenectomy was initiated in Japan.78 A prospective randomized trial of 62 patients with esophageal squamous cell cancer comparing 2-field with 3-field lymphadenectomy has been reported by Nishihara and colleagues.78 Recurrence rates were lower and survival improved in patients after 3-field dissection, but the small numbers precluded attaining significance. This occurred at the price of a significant increase in complications. Altorki and colleagues reported outcomes in a single-center prospective series of 80 patients (60% with 506

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TABLE 8. pTN classifications with similar survival, illustrating survival difference between minimal and extensive lymphadenectomy Extensive lymphadenectomy pT

Nodes positive

Nodes resected

5-yr risk-adjusted survival (%)

T1 T1 T2 T2 T3/T4 T3/T4

3-6 ⱖ7 3-6 ⱖ7 3-6 ⱖ7

ⱖ35 ⱖ35 ⱖ35 ⱖ35 ⱖ35 ⱖ35

40 28 28 21 23 15

Minimal lymphadenectomy pT

5-yr risk-adjusted survival (%)

Nodes resected

Nodes positive

T1 T1 T2 T2 T3/T4 T3/T4

42 31 31 20 21 14

⬍5 ⱕ10 ⱕ5 ⱕ10 ⱕ5 ⱕ10

1-2 3-6 1-2 3-6 1-2 3-6

Reprinted with permission from Rizk and colleagues.77

adenocarcinoma) undergoing esophagectomy with 3-field lymphadenectomy in the United States.34 Neck dissection was associated with a 36% incidence of cervical lymph node metastases regardless of the histologic type or tumor location. Five-year overall survival was excellent at 51%. European single-institution data have been reported by Lerut and colleagues.33 They assessed the impact of esophagectomy with 3-field lymphadenectomy on staging, morbidity, disease-free survival, and overall survival in 174 esophageal patients, 55% of whom had adenocarcinoma. Overall hospital mortality was 1.2%, and the overall morbidity was 58%. Five-year disease-free survival was 46.3%, and 5-year overall survival was 41.9%. These data confirm that 3-field resection can be performed with low mortality and acceptable morbidity, but they do not address the potential benefit of 3-field dissection compared directly to a 2-field dissection. To address this, a recent study by Shim and colleagues compared esophagectomy with 3-field vs 2-field dissection in 91 patients with squamous cell cancer (57 patients received 3-field and 34 2-field lymphadenectomy). No survival benefit was found in patients undergoing cervical nodal dissection.79 At the current time, the data leave the benefit of the routine addition of a cervical node dissection in doubt. Curr Probl Surg, August 2012

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Gastric Cancer D1 vs D2 vs D3 Lymphadenectomy. The benefits of lymphadenectomy in gastric cancer are relatively well established both with respect to surgical staging and long-term survival. Studies suggest that the reliable determination of the pN stage requires at least 16 lymph nodes analyzed in the surgical specimen.61 This requirement minimizes the risk of stage migration or the “Will Rogers phenomenon” with greater lymphadenectomy, whereby a metastatic lymph node may not be detected with a lesser resection resulting in an inaccurate stage of N0, when in fact removal of greater number of nodes would have shown that patient to be N1 or N2. Considerable data also show that greater lymphadenectomy in gastric cancer is associated with improved long-term survival and reduced local recurrence rates. Controversy remains, however, as to which type of lymph node dissection should ideally performed. Several prospective trials have assessed the prognostic differences between D1, D2, and D3 lymphadenectomy.60,80-85 One of the earliest multicenter observation trials was the German gastric cancer study. The trial included 1654 gastric cancer patients undergoing gastrectomy with D1 or D2 lymphadenectomy between 1986 and 1989.60 The D2 lymphadenectomy group had a significant survival benefit compared with those undergoing D1 lymphadenectomy, particularly in patients with Union for International Cancer Control (UICC) stages II and IIIA disease. Postsurgical morbidity and mortality rates were similar. The Dutch Gastric Cancer Study Group conducted a prospective randomized trial in the Netherlands between 1989 and 1993 further examining the benefit of extending the lymphadenectomy. This trial randomized 711 patients with gastric cancer who underwent treatment with curative intent (380 D1 and 331 D2).80 Initial analysis showed similar survival between the 2 groups, although long-term reanalysis showed a significant survival advantage in favor of D2 lymphadenectomy. However, D2 dissection in this trial included distal pancreatectomy and splenectomy in a substantial proportion of patients, which led to a significantly higher rate of complications than those in the D1 group, including more postoperative deaths and a longer hospital stay. Subgroup analysis excluding hospital deaths showed that patients with pN2 status undergoing D2 dissection enjoyed a significant overall and relapse-free survival advantage. It is widely acknowledged that the failure to show a significant overall survival benefit of D2 over D1 dissection is likely because of the hospital mortality rate after D2 dissection.81 A British Medical Research Council gastric cancer surgical group trial also failed to show a survival advantage for D2 508

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TABLE 9. Gastric cancer 5-year overall survival by disease stage and number of lymph nodes dissected

Number of lymph nodes dissected Disease stage T½ N0 T½ N1 T3 N0 T3 N1

1-10 (%)

11-20 (%)

21-30 (%)

31-40 (%)

>40 (%)

61 33 33 14

67 51 50 25

71 65 56 33

87 25 (n ⫽ 4) 58 42

93 70 83 50

Reprinted with permission from Smith and colleagues.91

lymphadenectomy mainly because of a high hospital mortality rate of 15% in patients undergoing a D2 dissection.82 McCulloch and colleagues reported a Cochrane review of both randomized and nonrandomized trial of gastric cancer examining both morbidity and survival. The authors concluded that D2 dissection has an increased mortality risk when coupled with spleen and or pancreatic resection. Nevertheless, there was evidence of an overall survival benefit after D2 resection in randomized studies with patients with locally advanced tumors and a possible survival benefit in intermediate UICC stages in nonrandomized studies.86 Despite the findings of these largely flawed trials and the difficulty in proving the benefit of lymphadenectomy in prospective randomized studies, there is a general consensus of the benefit of D2 lymphadenectomy particularly in areas of the world with a high prevalence of gastric cancer and experience to minimize the risk of perioperative complications, such as in Japan, Korea, and Germany. To date, 3 prospective randomized trials comparing D2 and a more extensive D3 gastrectomy (including pariaortic lymph node dissection) have been reported.87-90 All the 3 trials concluded that both D2 and D3 gastrectomy can be performed safely; however, D3 lymph node dissection did not achieve a survival benefit. Number of Resected Lymph Nodes. Similar to esophageal cancer, evidence suggests that the total number of surgically removed lymph nodes is independently associated with overall and disease-free survival in gastric cancer patients.91-93 Analyzing a large US-population database of gastric cancer patients, Smith and colleagues reported that overall survival was highly dependent on the number of lymph nodes examined in the surgical specimen (Table 9).91 A cut-point analysis yielded the greatest survival difference at 10 lymph nodes examined but continued to detect significantly superior survival differences for cut points up to 40 lymph nodes. Comparable findings were reported by Huang and colleagues investigating the long-term prognostic impact of the number of Curr Probl Surg, August 2012

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resected lymph nodes in patients with node-negative gastric cancer. The authors found that the total number of dissected lymph nodes was an independent prognostic factor with a long-term survival benefit in patients with more than 15 lymph nodes in the surgical specimen.93 As in esophageal cancer, this benefit of extended lymphadenectomy is postulated to be because of the removal of micrometastatic disease. Concomitant Resection of the Spleen and/or Pancreas. As mentioned earlier in the text, the British and Dutch trials on D2 lymphadenectomy in gastric cancer demonstrated that splenectomy was an important risk factor for postoperative morbidity and mortality.80-82 Nonrandomized case– control studies have also suggested a survival disadvantage after splenectomy in patients with gastric cancer. These data prompted Japanese investigators to conduct a phase III trial assessing the role of splenectomy in patients with total gastrectomy.94 Recruitment has been completed with inclusion of 505 patients (254 patients with and 251 without splenectomy), but final results are not yet reported. To date, no prospective study has proven a survival benefit for combined pancreaticosplenectomy with total gastrectomy in gastric cancer patients.80-82,87

Conclusions Three different paradigms have characterized the history and rationale for lymphadenectomy in esophageal and gastric cancer: (1) the mechanistic or Halstedian theory, (2) the systemic or Fisher theory, and (3) the current recognition that even within a single tumor type, its biology is heterogeneous and represents a spectrum of behavior. It has become clear that current rationale for lymphadenectomy serves 2 purposes, both for staging and therapeutic benefit. Esophageal cancer is well known to have variable lymphatic spread and skip metastases as a result of the extensive lymphatic channels within the esophagus. In contrast, lymphatic spread of gastric cancer is typically limited to the abdominal lymph node compartment alone. Although studies with direct comparison of resection with and without lymphadenectomy remain controversial, recent data strongly suggest that the total number of surgically removed lymph nodes is independently associated with improved overall and disease-free survival in both esophageal and gastric cancer patients. Controversies remain regarding which type of lymph node dissection should be performed. To date, the most common approach for extended lymphadenectomy in esophageal cancer is 2-field lymphadenectomy and in gastric cancer, gastrectomy with D2 lymphadenectomy. Controversy remains whether the increase of survival rates after extended lymph node dissection are because of stage migration, or a true therapeutic benefit. 510

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