Sentinel node navigation surgery in esophageal cancer

Abstract Over the last 20 years, the sentinel node (SN) concept has been widely applied to the surgical staging of both breast cancer and melanoma. However, the validity of this concept has been controversial for esophageal cancer, because SN mapping for esophageal cancer is not considered to be technically easy because of the complicated multidirectional lymphatic networks of the esophagus and mediastinum. Nevertheless, studies including meta‐analyses indicated that SN mapping may be feasible in early esophageal cancer. Transthoracic esophagectomy with three‐field lymphadenectomy was developed as a potential curative procedure for thoracic esophageal cancer. However, this highly invasive procedure might increase morbidity and reduce patients’ quality of life (QOL) after esophagectomy. Although further validation based on multicenter trials using the standard protocol of SN mapping for esophageal cancer is required, SN navigation surgery would enable us to carry out personalized and limited lymph node dissection which might reduce morbidity and maintain patients’ QOL.


| INTRODUCTION
Esophageal cancer is the eighth most common cancer worldwide, affecting more than 450 000 people per year and for which the incidence is increasing. 1 Esophageal cancer also has one of the highest malignant potentials of any tumor. Its primary therapy is selected according to histological type, tumor stage and location, and patient's performance status and comorbidities. 2 Although the efficacy of chemotherapy or chemoradiotherapy (CRT) for esophageal cancer has been reported, esophagectomy remains the mainstay of potential curative treatment for esophageal cancer. 2 Lymph node metastasis is known as one of the useful indicators for predicting the long-term outcome of esophageal cancer. Lymph node metastasis is not a rare event in esophageal cancer, with its incidence, even in submucosal tumors, reaching 45%. 3 Other specific characteristics of esophageal cancer are multidirectional lymphatic flow from the primary tumor site and widespread and random patterns of lymph node metastasis from the neck to the abdominal areas. In fact, it was reported that anatomical skip metastases to the second or third compartment of regional lymph nodes were found in more than half of esophageal cancer cases. 3 Middle thoracic esophageal cancer metastasized widely to the lymph nodes located from the neck (26%) to the abdomen (39%). 3 Considering these specific characteristics, total or subtotal esophagectomy with three-field lymphadenectomy has been recognized as a standard procedure for esophageal squamous cell carcinoma (SCC) in Japan. 3,4 However, esophagectomy with three-field lymphadenectomy is one of the most invasive procedures in gastrointestinal (GI) surgeries even by minimally invasive esophagectomy such as thoracoscopic and laparoscopic approaches. Postoperative complications and mortality are known to be remarkably increased by three-field lymphadenectomy. 5 Sentinel node (SN) mapping may play a significant role in reducing the need for the uniform application of the highly invasive surgery by providing personal information to allow modifications of the surgical procedure for esophageal cancer patients. The SN is defined as the first lymph node(s) receiving lymphatic drainage from the primary tumor site. 6 The SN is considered to be the first possible site of lymph node micrometastasis from the primary tumor. If the SN is recognizable and pathologically negative for cancer metastasis, unnecessary radical lymphadenectomy could be omitted. SN navigation surgery is a type of less invasive surgery with modified or minimized lymphadenectomy based on the diagnosis of SN metastasis.
Sentinel node mapping and biopsy were first applied to breast cancer and melanoma and subsequently attempted for other solid tumors including GI cancers. 6-10 SN mapping and biopsy results in reducing postoperative complications as a result of unnecessary extended lymphadenectomy in patients SN negative for cancer metastasis. 6,7 Sentinel node mapping for esophageal cancer is technically difficult in comparison with that for gastric cancer. 10 However, SN mapping and biopsy might become useful tools for the accurate intraoperative diagnosis of lymph node metastasis and modification of the surgical procedures in minimally invasive surgery in patients with early-stage esophageal cancer. 11

BIOPSY PROCEDURES IN ESOPHAGE AL CANCER
A radio-guided method is preferentially used to identify the SN in esophageal cancer. [10][11][12] In our institution, technetium-99m tin colloid solution as a radioisotope tracer is injected using an endoscopic puncture needle at four quadrants into the submucosal layer surrounding the primary tumor the day before surgery. Preoperative lymphoscintigraphy is usually carried out 3-4 hours after injecting the tracer (Figure 1). In terms of the distribution of SN, they are spread widely from cervical to abdominal areas.
We usually use a handheld gamma probe to accurately identify SN, which can be introduced from the trocar ports for thoracoscopic or laparoscopic intraoperative SN mapping ( Figure 2). SN located in the neck can be easily identified by percutaneous gamma probing. After intraoperative SN mapping and biopsy, all SN in the resected specimens are confirmed using the gamma probe on a back table near the   operating table and sent for intraoperative pathological examination. Finally, we confirm the absence of residual SN in the mediastinum or abdominal cavity using the gamma probe. In order to verify the accuracy of the SN mapping, intraoperative SN mapping and biopsy are generally followed by total or subtotal esophagectomy with regional lymphadenectomy based on the Japanese guidelines. 12 In contrast, a dual tracer method using radioactive tracer and blue dye (indocyanine green) is useful for SN detection for abdomi- Dye-only-guided SN mapping is not recommended for thoracic esophageal cancer because lymph nodes in the mediastinum are frequently pigmented by anthracosis. 13 Moreover, real-time observation of the lymphatics using blue dye is sometimes difficult without operative mobilization of the esophagus, but the mobilization itself may disturb active lymphatic flow from the primary tumor site. However, the blue dye in addition to the radio-guided method is useful in abdominal esophageal cancer or EG junction cancer, because it is relatively easy to identify blue-stained lymphatic vessels and lymph nodes without the mobilization of the esophagus in the abdominal cavity compared with that in the mediastinum. Furthermore, pigmentation as a result of anthracosis is relatively rare in abdominal lymph nodes.
Endoscopic submucosal injection of tracer is useful for accurate SN mapping of esophageal cancer. The radioactive tracer, technetium-99m tin colloid, has a relatively larger particle size (~200 nm in diameter) than blue dye. 14 The radioactive tracer is known to migrate into the SN from the primary lesion within 2 hours after injection and accumulates in the SN without excessive diffusion. Radioactivity lasting at least 20 hours is sufficient for SN detection. 15,16 Preoperative lymphoscintigraphy is useful for detecting SN distant from the primary lesion before surgery ( Figure 1). Furthermore, a handheld gamma probe is accurate and useful for intraoperative detection of SN in esophageal cancer. 12 Gamma probing was shown to be feasible even in thoracoscopic or laparoscopic SN mapping. 12

ESOPHAGEAL CANCER
To date, fewer studies have shown the feasibility and validity of the SN concept in esophageal cancer 10 (Table 1). However, a number of single institution studies have indicated acceptable outcomes of SN mapping and biopsy for early-stage esophageal cancer. 31 In particular, a radioguided method appears to be superior regarding the SN detection rate and accuracy at predicting lymph node metastasis compared to the conventional dye-guided method for esophageal cancer (Table 1).
Several types of radioisotope tracers have been used in SN studies for esophageal cancer (Table 1). 17,21,25 Specifically, particle size of the radiocolloid is thought to be related to the time of tracer deposition in the lymph node; therefore, a larger particle such as tin colloid would be associated with a longer period of deposition. SN mapping with technetium-99m colloidal rhenium sulfide was also reported to be useful to identify the lymphatic basin in 25 patients with esophageal cancer, and the results mostly matched those obtained with technetium-99m tin colloid. 17 However, further studies will be needed to ensure the optimal selection of radioisotope tracers.
Several contraindications against the recommendation of SN mapping in esophageal cancer have been reported. 11 Patients with clinically apparent lymph node metastasis should be excluded from the indication for SN mapping because the purpose of SN mapping is to identify clinically undetectable lymph node involvement.
Regarding tumor depth, clinically T1 esophageal cancers were reported to be suitable for SN mapping. 10 were mainly located in the lower and middle mediastinum and in the abdominal area in lower thoracic esophageal cancer, but some patients showed SN in the upper mediastinum. In more than 85% of patients with thoracic esophageal cancer, at least one SN was found to be located in the second or third compartment of regional lymph nodes. 12 Generally, the lymph node stations that were frequently identified as SN showed a tendency to have a high incidence of metastasis, as detected pathologically.
In another study, 70 patients who underwent radio-guided SN mapping and who were diagnosed with pathological T1 primary thoracic esophageal cancer were assessed in our institution. 28

MICROMETASTASIS IN SN OF ESOPHAGEAL CANCER
Even now, positron emission tomography (PET)/CT scans still have limited sensitivity in detecting micrometastasis in esophageal cancer compared with conventional pathological examinations. [36][37][38] Although SN mapping in esophageal cancer is clearly more invasive than other imaging, SN mapping and biopsy are believed to detect micrometastasis more accurately than other imaging procedures in patients with cN0 early-stage esophageal cancer. 28,39 Several studies have demonstrated underestimation of the frequency of micrometastasis in regional lymph nodes by conventional pathological diagnosis using hematoxylin and eosin staining. 40 In addition, immunohistochemical nodal micrometastasis is reported to be a significant prognostic indicator in patients with cN0 esophageal cancer. 41

MAPPING IN ESOPHAGEAL CANCER
Radical esophagectomy with extended three-field lymphadenectomy has been established as a potential curative surgical procedure for thoracic esophageal SCC in Japan. 1,2 Esophagectomy with three-field lymphadenectomy may be reasonable on account of the wide distribution of SN and unpredictable metastatic nodes. 12 were pathologically negative for cancer metastasis in patients with cT1N0 middle or lower thoracic esophageal cancer, cervical lymphadenectomy would be omitted. 12 However, we also consider that SN mapping and biopsy will even be applicable to two-field lymphadenectomy and provide useful information regarding the extent of lymphadenectomy. 12  Definitive CRT was reported to be a good option for patients with cT1N0M0 esophageal SCC who do not want surgical treatment. 50 However, how to design the optimal irradiation field is still controversial, because larger fields might be better regarding control of subclinical lymph node metastasis, but may result in more adverse effects during long-term follow up. 51 We have carried out concurrent CRT for 16 patients with cT1N0M0 esophageal SCC with minimized irradiation fields that contain SN identified by lymphoscintigraphy to achieve local control of subclinical metastasis in SN. 52

| CONCLUSION
The incidence of lymph node metastasis is relatively high even in cN0 early-stage esophageal cancer. Therefore, SN mapping must be accurate for carrying out SN navigation surgery in esophageal cancer. Previous studies suggested that the SN concept appears to be valid and radio-guided SN mapping may be feasible in cT1N0 esophageal cancer. Further accumulation of evidence based on multicenter trials using a standard protocol of SN mapping is needed, but SN navigation surgery will become an ideal less invasive personalized treatment for early-stage esophageal cancer.

DISCLOSURE
Conflicts of Interest: Authors declare no conflicts of interest for this article.