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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 238-242

Para-aortic lymph node tracing and dissection in advanced gastric cancer: Effectiveness of carbon nanoparticles injection through the no. 12b lymph node


1 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
2 Biomedical Engineering Center, Beijing University of Technology, Beijing, China

Date of Submission17-Jul-2019
Date of Decision03-Nov-2019
Date of Acceptance15-Nov-2019
Date of Web Publication28-May-2020

Correspondence Address:
Yuan Huang
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_506_19

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 > Abstract 


Background and Objectives: The relative effectiveness of tracers in guiding para-aortic lymph node dissection (PAND) in advanced gastric cancer is undefined. In this single-center, prospective study, we aimed to discuss the effectiveness of such tracers.
Materials and Methods: Between January 2015 and January 2016, 90 consecutive patients with stage T4a gastric cancer were evenly assigned to receive 0.2 mL of carbon nanoparticles (a), methylene blue (b), or no tracer (c) injection through no. 12b lymph nodes before PAND.
Results: There was no difference in the baseline characteristics between the three groups. Group A vs. B or C had a higher number of dissected lymph nodes (34.1 ± 9.8, 25.5 ± 5.5, and 22.6 ± 3.7; P < 0.001; B vs. C: P =0.321) and no. 16a2/b1 para-aortic lymph nodes (PANs; 11.8 ± 4.8, 7.0 ± 1.2, and 5.5 ± 1.2; P < 0.001; B vs. C: P =0.178) and similar rates of lymph node metastasis (20.9 ± 17.5%, 19.1 ± 15.1%, and 23.6 ± 19.7%; P = 0.511), positive dissected PAN (23.3% [7/30], 16.7% [5/30], and 16.7% [5/30]), surgery duration (252.9 + 35.4, 244.4 ± 29.0, and 250.3 + 29.9 min; P = 0.421), and blood loss (266.7 ± 115.5, 270.0 ± 82.6, and 260.0 ± 116.3 mL, P = 0.933). There was no common bile duct damage by tracer injection, and one case of duodenal stump fistula, one abdominal infection, and two anastomotic leakages in Groups A–C, respectively, were treated successfully.
Conclusions: In advanced gastric cancer treatment, carbon nanoparticle injection into no. 12b nodes appears to better trace no. 16a2/b1 PAN.

Keywords: Advanced gastric cancer, carbon nanoparticles, para-aortic lymph nodes, tracer agents


How to cite this article:
Mu G, Huang Y, Wei C, Chen Z, Wu X, Qin X, Zeng Y. Para-aortic lymph node tracing and dissection in advanced gastric cancer: Effectiveness of carbon nanoparticles injection through the no. 12b lymph node. J Can Res Ther 2020;16:238-42

How to cite this URL:
Mu G, Huang Y, Wei C, Chen Z, Wu X, Qin X, Zeng Y. Para-aortic lymph node tracing and dissection in advanced gastric cancer: Effectiveness of carbon nanoparticles injection through the no. 12b lymph node. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:238-42. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/238/285190




 > Introduction Top


Gastric cancer is the most common gastrointestinal malignancy in China, ranking the third in mortality and diagnosed mostly in advanced stages.[1] Gastric cancer most frequently metastasizes through lymph nodes, and standard D2 radical gastrectomy has been considered an effective treatment for advanced gastric carcinoma.[2] Para-aortic lymph nodes (PANs) are the last line of defense before lymph node metastases progress into the thoracic ducts. However, the effectiveness of D2 radical gastrectomy plus para-aortic lymph node dissection (PAND) in improving survival rate remains controversial.[3]

Sasako et al.[4] reported that D2 + PAND did not improve the survival rate of curable gastric cancer patients, and the Japanese Therapeutic Guideline for Gastric Cancer does not recommend preventive D2 + PAND. However, for cases with positive no. 16 lymph node metastasis without metastasis to other organs, D2 + PAND after neoadjuvant chemotherapy appears practical to achieve R0 resectability.[5] Tokunaga et al.[6] found it beneficial to selectively reserve PAND as a surgical approach for cases with positive metastasis in the PANs. Tsuburaya et al.[7] reported that D2 + PAND after neoadjuvant chemotherapy is effective for some specific patients. Nonetheless, the third edition of the NCCN guidelines for gastric cancer published in 2016 recommended against the use of D2 + PAND in curable patients (those with stages T2, T3, or T4),[8] while the fourth edition of the Japanese Guideline of Gastric Cancer Therapy (2014) indicated that comprehensive therapy with expanded dissection is optional in cases where swollen lymph nodes are limited to no. 16a2/b1 lymph nodes and without other incurability-related factors.

Keshari et al.[9] have reported that injecting carbon nanoparticles as a tracer agent around gastric cancer foci significantly improves lymph node detection without increasing mortality. Currently, carbon nanoparticle injection is mostly used in gastric oncology as a tracer agent to detect sentinel node and for D2 lymph node dissection.[9],[10] However, there are few reports on the use of tracer agents in PAND. The close proximity of PAN to important blood vessels including the postcava and the right renal vein, among others, renders PAND challenging; therefore, it is only advised to be performed by highly skilled surgeons at major medical centers.[11]

Searching for a method to accurately and safely dissect PAN is of high clinical value. Therefore, the present prospective single-center study aimed at comparatively investigating injection of newly developed carbon nanoparticles into no. 12b lymph nodes in contrast to injection of methylene blue or the use of no tracer to identify and dissect PAN in advanced gastric cancer.


 > Materials and Methods Top


Study design

Ninety gastric cancer patients who were preoperatively estimated to be T4a stage (TNM staging according to the seventh AJCC TNM staging standard)[12] treated in our research institution from January 2015 to January 2016 were included in this study and screened according to the following criteria: (1) preoperative gastroscopic pathology was gastric carcinoma; (2) preoperative abdominal multislice spiral computed tomography and electronic ultrasound gastroscopy indicated T4a stage; and (3) radical D2 + PAND was performed on the patient by the same surgical team. Meanwhile, patients with certain distant metastasis were excluded. Patients were evenly assigned to receive carbon nanoparticle injection through the no. 12b lymph node (Group A), methylene blue injection through the no. 12b lymph node (Group B), or no tracer (Group C), and each group included 30 cases. This study was approved by the ethical review committee on April 22, 2019 (Approval number: 2019 [KY-E-084)]).

Tracer agents

The preparation of carbon nanoparticles (Chongqing Laimei Pharmaceutical Co., Ltd., Chongqing, China) was a stable suspension solution (1 mL: 50 mg) of carbon nanoparticles (150 nm in diameter), which cannot enter the blood circulation and can be eliminated through the lungs or intestines. No acute systematic allergic reaction was caused by carbon nanoparticles. Methylene blue injection was prepared with 2 mL: 20 mg, a nontoxic small dose.

Para-aortic lymph node dissection surgical methods and quality control

During surgery, carbon nanoparticles or methylene blue was administered through the no. 12b lymph node. Guided by the black staining on the no. 16a2/b1 lymph node group, lymph nodes were dissected according to lymph node grouping and dissection areas in the Japanese Classification of Gastric Carcinoma (13th edition). For PAND, enlarged Kocher incision was made from the right side along the lateral side of the duodenum [Figure 1]a. Then, 0.2 mL of carbon nanoparticles or methylene blue was injected into the no. 12b lymph node [Figure 1]b and [Figure 2]a. An image of the stained no. 16a2/b1 lymph chain is shown in [Figure 1]c. Subsequently, the no. 16a2/b1 lymph nodes were dissected [Figure 1]d and [Figure 2]b. After PAND, no. 12b lymph nodes were biopsied.
Figure 1: Staining of no. 16a2/b1 nodes by carbon nanoparticles injected into the no. 12b node. Before (a); during (b), and after (c) tracer injection. Appearance after PAND (d)

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Figure 2: Staining of no. 16a2/b1 nodes by methylene blue injected into no. 12b node during (a) tracer injection and after lymph node dissection (b)

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Outcome evaluation

The differences in the total number of lymph nodes dissected, lymph node metastasis rate, number of PAN dissected, PAN metastasis rate, blood loss, operation time, and postoperative complications, including lymphatic leakage, anastomotic fistula, pancreatic leakage, anastomotic bleeding, and infection of the incision, were compared between the three groups.

Statistical analysis

SPSS 19.0 (Chicago, IL, United States) was used for all statistical analyses. Continuous data are presented as mean ± standard deviation or median and interquartile range and were compared by one-way analysis of variance. Categorical data are presented as number and percentage and were compared using the Chi-square test. P < 0.05 indicated a statistically significant difference.


 > Results Top


As shown in [Table 1], patient baseline characteristics were similarly distributed among the three groups. Overall, Group A vs. B or C had a higher mean number of dissected lymph nodes (34.1 ± 9.8, 25.5 ± 5.5, and 22.6 ± 3.7; P = 0.000 for A vs. B and A vs. C; P = 0.321 for B vs. C) and PAN (11.8 ± 4.8, 7.0 ± 1.2, and 5.5 ± 1.2; P = 0.000 for A vs. B and A vs. C; P = 0.178 for B vs. C). The rate of lymph node metastasis was 20.9 ± 17.5%, 19.1 ± 15.1%, and 23.6 ± 19.7% (P = 0.511) in Groups A to C, respectively; the mean positive rate of dissected PAN was 23.3% (7/30), 16.7% (5/30), and 16.7% (5/30), respectively. The mean surgery duration was 252.9 + 35.4 min, 244.4 ± 29.0 min, and 250.3 + 29.9 min (P = 0.421), respectively. The mean intraoperative blood loss volume was 266.7 ± 115.5 mL, 270.0 ± 82.6 mL, and 260.0 ± 116.3 mL, respectively (P = 0.933) [Table 2]. One patient in Group A developed a duodenal stump fistula, one patient in Group B developed an abdominal infection, and two patients in Group C developed anastomotic leakages. These patients were successfully treated. No damage was apparent to the common bile duct by the tracer injection. All no. 12b lymph nodes were biopsied and all were negative.
Table 1: Baseline characteristics of patients studied according to the tracer agent group

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Table 2: Study outcomes by tracer agent group

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 > Discussion Top


In the present prospective single-center study, injection through lymph node no. 12b of carbon nanoparticles was associated with an overall higher number of traced lymph nodes and dissected no. 16a2/b1 PAN in contrast to injection of methylene blue or the use of no tracer. PAND in advanced gastric cancer has always been a controversial topic.[3],[4],[5] One of the generally accepted opinions indicates that comprehensive therapy comprising surgical rectomy with expanded dissection is optional for patients in whom swollen lymph nodes are limited to the no. 16a2/b1 lymph nodes and those without other incurability-related factors. The PAN is the last barrier against gastric cancer-associated lymph node metastasis to the thoracic ducts, and metastasis to any other lymph nodes suggests the possibility of metastasis in PANs.[13] The 16.7%–23.3% metastatic rate in no. 16 lymph nodes in this study was consistent with that reported previously (6%–33%).[14] The JOCG9501 trial[15] showed that no. 16 lymph nodes are associated with the maximum tumor size, N staging, and metastasis in the left gastric artery, with the consideration that there are several possible routes of lymph nodes refluxing to the PANs including the left celiac artery lymph nodes, para-splenic artery lymph nodes, celiac trunk artery lymph nodes, superior mesenteric artery lymph nodes, and the lymph nodes behind the pancreatic head and common hepatic artery.

Several lymph node tracer agents have been developed over time including blue stain[16],[17] and indocyanine green[18] and the recent carbon nanoparticles.[10] Compared to other tracer agents such as methylene blue, carbon nanoparticles preferentially trace the lymphatic system and therefore act as ideal tracer agents for lymph nodes. Carbon nanoparticles are small enough to pass through the lymph capillary endothelium but big enough not to traverse the vascular endothelium. Because of the undeveloped basement membrane of the lymph capillary, carbon nanoparticles can only access the lymphatic circulation through macrophage ingestion rather than through hematogenous circulation; thus, as a tracer agent, carbon nanoparticles can stain the lymph node area dark while highlighting the lymphatic circulation.[19]

In the report by Keshari et al.,[9] the total number of lymph nodes dissected was 772 (35.41 in average) in the carbon nanoparticle group and 482 (26.78 in average) in the control group (P = 0.046), indicating that injection of carbon nanoparticles in a gastric tumor area could improve lymph node detection with good safety and effectiveness. The study by Yan et al.[10] revealed that using carbon nanoparticles injection, sentinel nodes can be more effectively and safely detected in early-stage gastric cancer. Applying a highly efficient tracer agent could increase the total number of lymph nodes dissected, eventually helping improve the accuracy of cancer staging and postoperative individual treatment plans. According to the results of our study, carbon nanoparticles were effective in improving lymph node detection and dissection, corroborating the results of the above studies. However, whether carbon nanoparticles are effective for tracing PAN remains unclear. Theoretically, injecting carbon nanoparticles through the submucosa or subserosa of tumors can also stain PANs; however, we posit that the effectiveness may be hampered by long circulation pathways and blockage of lymphatic vessels by the tumor. The following reasons were considered when deciding to inject carbon nanoparticles through the no. 12b lymph node to trace PAN in this study: (1) the anatomical location of no. 12b lymph node is relatively constant, and thus, it is easy to find after entering the abdominal cavity and convenient for injection; (2) the no. 12b lymph node has a short route to the PAN region, which is conducive for rapid and clear PAN display after tracer injection; and (3) the no. 12b lymph node is not recommended to be dissected in radical lymphadenectomy of gastric cancer according to the Guideline of the Japanese Gastric Cancer Association (3rd edition, 2016).[8] Thus, we deduced that the metastatic rate of the no. 12b lymph nodes is low, and when tracers are injected through the no. 12b lymph nodes, the possibility for needle-path metastasis is low. In this study, all no. 12b lymph nodes biopsied in the patients injected with a tracer were negative, which is consistent with the guideline recommendations.

In this study, the number of PAN dissected significantly increased after injecting carbon nanoparticles through the no. 12b lymph node when compared to that with the injection of methylene blue or the use of no tracer, while there was no significant difference between the latter groups. The results suggest that intraoperative application of carbon nanoparticle tracers was much better than methylene blue for PAND. Carbon nanoparticles injected through the no. 12b lymph nodes could clearly highlight the PAN and peripheral lymphatic network for thorough dissection of the PAN while minimizing postoperative lymphatic leakage and other major complications. There were no significant differences in average blood loss and operation time between the carbon nanoparticle, methylene blue, and control groups. This result may be attributable to all surgeries being performed by the same experienced, highly skilled surgical team and the use of energy devices such as an ultrasonic scalpel. Although there were no significant differences in the average blood loss and operation time, we believe that injecting carbon nanoparticles through the no. 12b lymph node can rapidly show black staining of the PAN intraoperatively, which is conducive for a safe surgery with fewer risks. This method, with a shorter learning curve, may also help beginners. In addition, the value of imaging and dissection of PAN after injecting carbon nanoparticles around gastric tumors should also be noted. As this study was limited to a small sample, further multicenter, prospective control study with a large sample is required to further evaluate the clinical value of carbon nanoparticles as tracer agents for PAND in gastric cancer.


 > Conclusions Top


Injecting carbon nanoparticles through no. 12b lymph nodes in gastric cancer patients appears to better trace the PANs, leading to a more accurate dissection of these nodes, and could eventually be of benefit to patients with metastasis to these nodes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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