0218492309103332.pdf

INVITED REVIEW

Current Trends in Extended Lymph Node Dissection for Esophageal Carcinoma Wen-Tao Fang, MD, Wen-Hu Chen, MD Department of Thoracic Surgery Shanghai Chest Hospital, Jiaotong University Medical School Shanghai, China

ABSTRACT Extended lymph node dissection helps increase the curativeness of resection, the accuracy of surgical-pathological staging, and the prognosis of thoracic esophageal carcinoma. However, it is also associated with significantly increased surgical morbidity and has noticeable negative effects on the quality of life after surgery. Current trends for selective lymph node dissection based on clinical evidence may be helpful in reducing surgical risks while assuring the completeness of resection. (Asian Cardiovasc Thorac Ann 2009;17:208–13)

KEYWORDS: Esophageal Neoplasms, Lymphatic Metastasis, Neck Dissection, Postoperative Complications, Vocal Cord Paralysis

INTRODUCTION Until now, radical resection has remained the most effective means of cure for esophageal cancer. However, the long-term outcome after routine esophagectomy is far from satisfactory, with 5-year survival rates at 20%–30%.1–4 Lymph node status is one of the most important prognostic factors for esophageal cancer. Upon presentation with dysphagia, over 70% of patients will already have lymph node metastasis.5 Of those who survive surgery, 80% will eventually die from tumor recurrence; at least 40% of these are due to recurrence in lymph nodes.6 Therefore, esophageal carcinoma should be considered at least as a local-regional disease, with all the regional lymph nodes included, instead of a localized lesion per se in the esophagus. Reducing local-regional recurrence and thus improving the quality of life is as important as gaining long-term survival.

MERITS OF EXTENDED LYMPH NODE DISSECTION FOR ESOPHAGEAL CANCER It has already been established that lymph nodes metastasis from esophageal cancer may occur at an early stage and skip to nodes far away from the primary tumor.7–9 Theoretically, if all the involved regional nodes could be completely removed along with the tumor itself, the chance of cure would be increased, and the risk of early local-regional recurrence reduced

significantly. On the other hand, with metastatic nodes left behind, not only might the disease be under-staged, but the curativeness of surgery should also be questioned. Given that postoperative chemotherapy has shown little survival benefit, and the lack of other effective adjuvant therapies, it is not surprising to observe a high recurrence rate in mediastinal or cervical lymph nodes shortly after surgery.10,11 Such patients often present with hoarseness or dyspnea caused by depression of the recurrent laryngeal nerve or major airway from enlarged lymph nodes. Apart from a dismal survival, the quality of life in these patients is also jeopardized. While esophageal cancer is considered more or less a systemic disease in Western nations, and treated mainly with concurrent chemoradiotherapy, it is taken as a local-regional disease in other parts of the world, especially in Asian countries like Japan and China. Based on this principle, clinical trials of systemic lymph node dissection have been widely carried out since the early 1980s. The extent of lymph node clearance was first extended from the original mid and inferior mediastinum to the superior mediastinum so as to remove the lymph nodes along bilateral recurrent laryngeal nerves. Then it was further extended into the neck; lymph nodes along the cervical part of the

Fang Wen-Tao, MD Tel: +86 21 62821990 Fax: +86 21 68201190 Email: [email protected] Department of Thoracic Surgery, Shanghai Chest Hospital, 241 Huaihai Road West, Shanghai, 200030, China. doi: 10.1177/0218492309103332 ß SAGE Publications 2009 Los Angeles, London, New Delhi and Singapore ASIAN CARDIOVASCULAR & THORACIC ANNALS 2009, VOL. 17, NO. 2 208

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recurrent nerves and those located lateral to the cervical vessels were also dissected. Although the optimal extent of lymph node clearance has always been under debate, the superiority of extended lymphadenectomy has rendered it a standard procedure in more than 70% of institutions in Japan.7,12 It is also interesting to note that quite a few leading institutions in Western nations have also joined in the practice, with similar results to those obtained in Japan, despite an increased incidence of adenocarcinoma in their populations.13,14

longitudinal rather than across the muscle layer of the esophageal wall. Lymphs from above the carina mainly go upward to the superior mediastinum and neck, whereas lymphs below the carina go downward via the mid and inferior mediastinum to the left gastric and celiac nodes.17 Therefore, superior mediastinal nodes are most commonly involved in upper esophageal tumors, while mid-mediastinal nodes are most often involved in middle esophageal tumors, and inferior and abdominal nodes are most frequently involved in tumors located in the lower third of the esophagus.9 Lymph node stations most often involved in thoracic esophageal carcinoma, such as the nodes along the cervical and mediastinal part of the recurrent nerves, under the carina, and at the peri-cardiac and left gastric artery, may all be included as periesophageal nodes.

The benefit of systemic lymph node dissection is based mainly on 3 factors. Firstly, it provides more accurate tumor staging. It was through systemic dissection that lymph node metastasis was clinically proved to be a common phenomenon in esophageal cancer. The Japanese Association of Esophageal Oncology Group carried out a nationwide survey on lymphadenectomy among 96 institutions in 1991.7 The results showed that the rate of lymph node metastasis was 58.7% after 2-field (thoraco-abdominal) dissection. It increased to 72.9% after adding cervical dissection, making the procedure a 3-field (cervico-thoraco-abdominal) one. It is noteworthy that apart from a 27.4% rate of cervical metastasis, the rate of mediastinal metastasis was also significantly increased from 40.8% after 2-field dissection to 55.8% after 3-field dissection, indicating more thorough lymph node clearance in the superior mediastinum, especially the cervical-mediastinal junction. At the same time, there was a significant upstaging of the diseases after lymph node dissection was extended further into the neck. The only prospective randomized clinical trial comparing the results of 3-field and 2-field dissections showed a 26% rate of cervical metastasis from thoracic esophageal squamous cell carcinoma.12 It is worth mentioning that another clinical trial of 3-field dissection by Altorki and colleagues14 also yielded a 70% regional lymph node metastasis rate and a 35% cervical metastasis rate. In that trial, however, the original lesions included both squamous carcinoma and adenocarcinoma located in the distal esophagus.

Thirdly, with more metastatic nodes removed at surgery, the curativeness of resection has also been improved. Although there have been few, if any, strictly designed phase III trials comparing the long-term results of lymph node dissection, the reported 5-year survival rates after 3-field dissection have been without exception in the range of 40%–50%.7,8,13 On the contrary, 5-year survival rates after routine procedures such as Ivor-Lewis or transhiatal esophagectomies seldom reach over 30%. The merit of removing all potentially involved lymph nodes lies also in the fact that recurrence in localregional lymph nodes could be significantly reduced after extended dissection. The quality of life for patients is therefore improved dramatically. This has been proved by studies of recurrence patterns after esophagectomy (Table 1). A detailed review of the literature revealed that although distant metastasis remained unchanged, the rates of local-regional recurrence after systemic nodal dissection, be it 2-field or 3-field, were usually less than 20%, while it was in the range of 30%– 40% after routine esophagectomy.18–24 Kato and colleagues18 reported that similar rates of distant metastasis occurred regardless of whether or not neck and superior mediastinal nodes were removed (16% and 17%). However, with 3-field dissection, local recurrence was reduced to 17% in contrast to routine esophagectomy which was as high as 38%. It was noteworthy that relapse in mediastinal nodes was reduced from 23% to 11%, and in cervical nodes from 12% to 2%. The autopsy study by Katayama and colleagues25 also revealed that local recurrence was significantly lower after subtotal esophagectomy with lymph node dissection (19.4%) than a partial esophagectomy per se (66.7%). The benefit of reducing local recurrence is also possibly in the management of adenocarcinoma of the esophagus. Hagen and colleagues21 found that among 10 local-regional relapses in 100 esophageal

Secondly, the knowledge we now posses of the characteristics of lymphatic metastasis from esophageal cancer could not have been fully gained had it not been for the practice of systemic dissection. The abundance of lymphatics in the submucosal layer provides the anatomical basis for lymph node metastasis from esophageal cancer to occur at an early stage.15–17 According to the results of extended lymph node dissection, regional node metastasis may reach 25%–30% when the tumor invades the submucosa, and increases gradually with the depth of tumor invasion.7,8 The specific architecture of the lymphatics of the submucosa also makes lymph flow more preferentially 2009, VOL. 17, NO. 2

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Recurrent laryngeal nerve palsy is the most often mentioned complication directly related to cervical and superior mediastinal dissection. In the abovementioned national survey by the Japanese Association of Esophageal Oncology Group, the only significantly increased postoperative complication after 3-field dissection was recurrent nerve paralysis.7 In one of the few controlled studies comparing different extents of nodal dissection, an astounding 53% rate of tracheotomy after 3-field dissection was documented. In a prospective trial, Fang and colleagues28 also found a significantly higher rate of recurrent nerve palsy in the 3-field group (22.9%) than in the 2-field group (9.6%). Furthermore, they noticed that it was significantly related to anastomotic leakage (53.8% vs. 13.5%), another major problem in most reports concerning 3-field dissection. The reason for this relationship was attributed to the increased but ineffective cough in patients having recurrent nerve injury during dissection. This may cause incessant compression on the stomach located in the anterior mediastinum and hence increased tension on the cervical anastomosis.29 They also found increased (although not significantly) pulmonary and cardiac complications after 3-field dissection compared to 2-field dissection. Besides, recurrent nerve palsy would have a significant impact on quality of life in the long run, in terms of speech, swallowing, and respiratory functions.30 All these have become major obstacles to an even wider application of extended nodal dissection.

DISADVANTAGES OF 3-FIELD DISSECTION Although there is now less doubt about the benefits of extended lymph node dissection, the optimal extent of dissection has always been controversial.12,25,26 As with similar procedures in the management of other malignancies, systemic dissection is a double-bladed sward. The greater the extent of dissection, the better the prognosis and local control might be; but the higher would be the surgical risks. If the mortality rates have been repeatedly reported to be similar, it is mainly because almost all of these reports were based on historical controls.7,12,25 In fact, complications directly related to surgical maneuvers, such as recurrent nerve palsy and anastomotic leakage, are far more common after 3-field dissection than after 2-field dissection (Table 2). In a parallel study comparing the results from 2 referral centers in Japan and China in the same time period, the overall morbidity rate was 64% after 3-field dissection, significantly higher than the 41.7% after 2-field dissection.27

Table 1. Recurrence patterns after esophagectomy with or without lymph node dissection Lymph Node Recurrence Author 18

Kato Nakagawa19 Dresner20 Hagen21 Hulscher22 Clark23 Katayama24 (autopsy)

No. of Cases

Extent of Dissection

Overall Recurrence

Distant Metastasis

Local Recurrence

160 171 212 100 137 38 43

3-field 3-field 2-field 2-field Transhiatal Sampling Dissection Sampling

36.8% 43.3% 42%

49% 16.9% 18% 31% 29.2%

18% 20.3% 23% 10% 37.3% 40% 19.4% 66.7%

52.6% 53% 62.8%

39.5%

Neck

Chest

Abdomen

2%

3%

3%

8% 7.9% 11.6%

21% 37.2%

24% 16.3%

Table 2. Surgical morbidity in 2-field and 3-field lymph node dissection

Variable Extent of dissection No. of cases Overall morbidity Recurrent nerve palsy Anastomotic leakage

Isono7 (Questionnaire Survey)

Fang27 (Comparative Study)

Kato12 (Controlled Study)

3-field 1,791 53.9% 20.3%

3-field 50 64.0% 10.0% 36.0%

3-field 77 62.3% 14.3% 33.8%

2-field 2,799 56.0% 14.0%

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2-field 48 41.7% 14.0% 22.9%

2-field 73 75.3% 20.5% 23.3%

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CURRENT TREND TOWARD SELECTIVE APPROACHES IN LYMPH NODE DISSECTION

only to a very small proportion of surgical candidates, as most patients presenting with symptoms would already be in a locally advanced stage. Even tumors invading only the submucosal layer would have a cervical metastasis rate of over 15%.32 Secondly, according to the current edition of the International Union Against Cancer classification for esophageal cancer, cervical lymphadenopathy is defined as M1a for tumors located at the upper thoracic esophagus, and as M1b for those located at the middle and lower esophagus, indicating a possibly different prognostic significance. So far there is no evidence that cervical dissection would be beneficial to upper esophageal tumors only. On the contrary, metastasis to the neck lymph nodes is equally common in tumors located at the upper and middle esophagus.33 As mentioned above, even for adenocarcinomas at the lower third of the esophagus, metastasis could reach 30%.14 Thirdly, as with the recent trends in breast cancer surgery, a ‘‘sentinel lymph node’’ is another appealing proposal.34 However, esophageal cancer contrasts anatomically with breast cancer in the means of lymphatic drainage. Until now, it has been impossible to identify a sentinel nodal station for cervical metastasis. Besides, it is technically unfeasible to add a second-stage cervical dissection if the anastomosis was located high in the neck during the first-stage operation, instead of an intrathoracic anastomosis as proposed by Noguchi and colleagues.34

Esophageal squamous cell carcinoma bears a significant similarity to breast cancer in that the prognosis is largely depended on the regional lymph node status. For a long time, nodal status of breast cancer was determined by axillary lymph node dissection, which was also associated with significant morbidity. Therefore, a reasonable selection of dissection extent so as to diminish the surgical risks while still assuring the completeness of resection is the key to the problem. As with the situation in the management of breast cancer in recent years, there is also a trend toward limited lymph node dissection in the surgical treatment of esophageal cancer. In a well-presented review of the merits and demerits of lymph node dissection, Law and Wong26 proposed that 2-field dissection might be enough. There were 2 reasons supporting this hypothesis. First, patients with cervical metastasis had such a poor prognosis that this subgroup might not benefit from the additional dissection. However, this has been repeatedly disproved. Occult cervical metastasis carries a different prognosis from palpable neck lymphadenopathy. Tachimori and colleagues31 reported that after 3-field dissection, the 3year survival of patients with occult cervical lymphadenopathy reached 43.8%, and it was significantly better than the survival rate in patients with palpable cervical nodes. Fang and colleagues28 also reported that 2-year survival of patients with impalpable cervical metastasis could reach 50%, comparable to that in patients with local nodal disease only. The second reason for confining the extent of dissection to the thoracoabdominal region is that most cervical metastases are along the recurrent nerve chain and might be dissected through the chest. Technically, lymph nodes along the right recurrent nerve can be easily removed from the thoracic cavity. However, lymph nodes at the left cervicalthoracic junction are far more difficult to access during the chest maneuver. Unfortunately, the metastasis rate on both sides are almost similar for thoracic esophageal lesions.8,9

In addition, selective lymph node dissection based on preoperative ultrasonography seems to be a more rational proposal. It has already been used in the surgical management of other malignancies such as melanoma, breast cancer, and head and neck cancers.35–37 Fang and colleagues28 proposed selective neck dissection based on cervical ultrasonography because the sensitivity and accuracy of ultrasonography for impalpable cervical lymphadenopathy could be as high as 80%–90%.31,38,39 Nearly 60% of their patients with negative ultrasonography were spared the more invasive neck dissection and thus the potential morbidities including recurrent laryngeal nerve palsy. The yield of metastatic cervical nodes (19.5%) was in the same range as in the series of Tachimori and colleagues31 (22.9%) where all patients received neck dissection irrespective of the result of ultrasonography.

Therefore, 3-field dissection should not be abandoned, but it should be carried out reasonably so as to tailor the procedure to patients individually. The underlying philosophy is to minimize the surgical risks while still retaining the merits of lymph node dissection. Attempts have already been made in several ways to pursue selective approaches in 3-field lymphadenectomy.28,32–34 Firstly, most studies on lymph node metastasis in esophageal cancer revealed that the extent of lymphatic involvement is related to the depth of tumor invasion. Early superficial cancers confined to the mucosa seldom metastasis to cervical nodes, and thus could be exempted from cervical dissection. However, this would apply 2009, VOL. 17, NO. 2

For ethical reasons, it is impossible to carry out prospectively randomized studies comparing the results of selective 3-field dissection with routine 3-field dissection. However, in recent years there has been accumulating evidence suggesting a trend toward a reasonable selection of dissection. Contemplation of a surgical indication should always take into consideration both the progressiveness of the tumor and the patients’ 211

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with three-field lymph node dissection. J Surg Oncol 1996; 61:267–72.

tolerance of the procedure. The solution to these problems lies in how to select appropriate candidates for 3-field dissection so as to maximize the benefits and minimize the risks, rather than to linger on the so-called optimal extent of dissection. Future studies are expected to add more evidence and help elucidate the problem.

19. Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T. Hatakeyama K. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg 2004; 198:205–11. 20. Dresner SM, Wayman J, Shenfine J, Harris A, Hayes N, Griffin SM. Pattern of recurrence following subtotal oesophagectomy with two field lymphadenectomy. Br J Surg 2000; 87:362–73.

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