Which lymph node dissection should be performed in advanced distal gastric cancer? A critical assessment of D2 lymphadenectomy

Abstract

Lymph node invasion stands out as the most critical prognostic factor in gastric cancer. The extent of lymph node dissection required during curative gastric cancer surgery has long been debated. Japanese Gastric Cancer Association was the first to define a classification system for regional gastric lymph node stations, numbering them from No. 1 to No. 16. This classification was later used to differentiate between different types of lymph node dissection, such as D1, D2 and D3. However, these definitions were often considered too complex to be universally adopted, resulting in wide variations of recommendations from one country to another and making it difficult to compare published studies. Moreover, the optimal extent of lymph node dissection remains uncertain, as the extensive dissections that where initially recommended are associated with significant morbidity without a clear survival benefit. Though gastrectomy with extended D2 lymphadenectomy is classified as a non-standard gastrectomy, its clinical significance has been evaluated in many studies. D2 plus superior mesenteric vein lymph node (No. 14v) dissection is recommended when metastasis to No. 6 nodes is suspected in the lower stomach, and D2 plus posterior surface of the pancreatic head (No. 13) lymph node dissection may be an option in potentially curative gastrectomy for cancer invading the duodenum. No. 14v lymph node dissection has been shown to improve overall survival in patients with distal gastric cancer, primarily in patients with clinical stage III/IV distal gastric cancer. Furthermore, D2 plus lymphadenectomy showed a significantly higher 5-year overall survival rate (55.3% vs 43.9%) and a lower recurrence rate (51.5% vs 69.5%) then D2 standard dissection. The quality of lymphadenectomy may influence prognosis in gastric cancer patients. Both hospital volume and surgeon volume were important factors for the quality of radical gastrectomy. The purpose of this review is to support the extension of lymph node dissection based on the existing literature, including a comprehensive review of current definitions of lymphadenectomy. An outcome analysis is performed to assess the need for lymphadenectomy with removal of lymph nodes not included in the standard D2 lymphadenectomy in patients with distal gastric cancer, especially if the tumor is advanced.

Key Words: Gastric cancer; Lymph node dissection; Lymph nodes metastases; Guidelines; Surgery

Core Tip: The extent of lymphadenectomy influences the prognosis in patients with distal gastric cancer. The most authoritative guidelines recommend a D2 lymphadenectomy in T2-T4 tumors, as well as T1N+, regardless of tumor location. The purpose of this review is to support the extension of lymph node dissection based on the existing literature. An analysis of the results is performed to assess the need for lymphadenectomy with removal of lymph nodes not included in the standard D2 lymphadenectomy in patients with distal gastric cancer, especially if the tumor is advanced.

INTRODUCTION

Lymph node metastasis is the main prognostic factor in gastric cancer[1]. Therefore, appropriate lymphadenectomy is essential in the therapeutic approach to gastric cancer patients[2-4]. The classification of gastric lymph nodes was codified by the Japanese Society for Gastric Cancer Research in 1981[5]. This subdivision is the most precise and analytical and classifies lymphatic drainage based on the location of the primary tumor. The Japanese authors also classified the extension of lymphadenectomy into D1, D2 and D3 in relation to the removed lymph node stations.

The American Joint Committee on Cancer tumor-node-metastasis (TNM) classification in 1987 (4^th edition) defined regional lymph node involvement based on the anatomic location of positive lymph nodes relative to the primary tumor. The system classified nodes within 3 cm of the tumor as N1 and those further away as N2, and these definitions allowed for more reliable prognosis estimation and facilitated international data comparison[6]. In the 1997 TNM classification (5^th edition), the main change was the transition from location-based to number-based N staging[7]. In this edition, greater emphasis is placed on the total number of metastatic lymph nodes[8]. This change was implemented to improve prognostic accuracy and led to new N categories and staging groups. Contrary to what is reported in the previous edition, the 5^th edition includes regional lymph nodes in a single class, also grouping together lymph nodes that, according to the Japanese classification, are of second and even third[9]. Furthermore, removal of at least 16 lymph nodes is recommended. The disparity in the classifications adopted and the changes made to the TNM have made it difficult to compare the results relating to the benefits of lymphadenectomy. Moreover, the results of several studies suggest that assessing 16 lymph nodes in gastric cancer may be inadequate both for accurate nodal staging and for improving patient survival.

The problem of comparing different case studies has been overcome by starting from the assumption that in a D1 lymphadenectomy a variable number of lymph nodes between 15 and 18 are removed, while in a D2 dissection an average of 31 to 35 are removed[10-12]. These findings led some authors to distinguish between a “standard” lymphadenectomy, which includes at least 16 lymph nodes and is the one which, according to the TNM, allows an adequate staging, and an “extended” lymphadenectomy, which includes at least 20-25 lymph nodes and allows a N3 staging and a better survival rate[13]. Further randomized trials are hampered by Western surgeons’ limited familiarity with extended lymphadenectomy, which has led to excessive postoperative morbidity, and by limited accuracy in distinguishing D1 from D2, with compliance and contamination issues[14].

Attempting to compare the two procedures by disease stage encounters several methodological difficulties, the most insidious of which is the so-called stage migration phenomenon[15,16]. The accuracy of staging is affected by the extent of lymphadenectomy: Patients staged as N- after limited lymphadenectomy are more likely to have undiagnosed lymph node metastases than those classified as N- after extended lymphadenectomy. Therefore, patients who undergo limited lymphadenectomy are more likely to have under-staging of lymph node involvement than those who undergo extended lymphadenectomy. The therapeutic successes of extended lymphadenectomy could therefore be explained, by the fact that when a stage-by-stage comparison is made, the disease stages compared are different. Despite that the guidelines recommend D2 lymph node dissection[17,18] for T1N+ or T2-T4 patients with distal gastric cancer, some believe that a D2 lymphadenectomy is not always the best solution for patients with distal advanced gastric cancer[19,20]. Likewise, it does not seem appropriate to define a lymphadenectomy involving 16 lymph nodes as adequate. Although D2 lymphadenectomy is considered the standard of care in potentially curative surgery guidelines for distal gastric cancer, the extent of lymph node dissection should be determined from the site and clinical stage of the tumor and should aim for a resection without residual disease.

The aim of this review is to highlight aspects related to lymphatic flows in the distal stomach, to develop arguments supporting a modified extension of lymph node dissection to include stations not included in the standard D2 lymphadenectomy in patients with distal gastric cancer. It also highlights some aspects that may lead to considering the distal stomach, and especially the pyloric region as an antroduodenal junction cancer and create a new classification like that already used for the esophagogastric junction.

DISTAL GASTRIC CANCER AND LYMPH NODES

In gastric cancer, different regional lymph node stations are described (Figure 1). The anatomical and functional information, also correlated with the incidence data of metastasis in each of the lymph node stations (Table 1), allowed us to group the 16 stations into 4 different groupings (from N1 to N4) with homogeneous prognostic significance[5]. While the involvement of the fourth level (N4) represented by stations Nos. 14a, 15, 16, 19, and 20 is consistently indicated as M+ regardless of the primary site of tumor, the first 3 groups vary depending on the site of the disease. For distal gastric cancer, stations Nos. 3, 4sa, 4sb, 4d, 5, and 6 are N1 (Figure 2A), stations Nos. 1, 7, 8a, and 9 are N2 (Figure 2B), and stations Nos. 2, 10, 11, 12a, 12b, 12p, 8p, 14v, and 13 constitute the N3 group (Figure 2C).

Figure 1 Anatomical definitions of lymph node stations according to the first classification of the Japanese Research Society for Gastric Cancer[5]. First region (highlighted in green). No. 1: Right paracardial. No. 2: Left paracardial. No. 3: Gastric lesser curvature. No. 4: Gastric greater curvature divided into No. 4sa (short vessels), No. 4sb (left gastroepiploic artery), No. 4d (right gastroepiploic artery). No. 5: Suprapyloric. No. 6: Infrapyloric. Second region (highlighted in yellow). No. 7: Left gastric artery. No. 8: Common hepatic artery divided into No. 8a (Anterior), No. 8p (posterior). No. 9: Celiac trunk. No. 10: Splenic hilum. No. 11: Splenic artery divided into No. 11p (proximal), No. 11d (distal). No. 12: Pedicle of liver divided into No. 12a (artery), No. 12b (bile duct), No. 12v (portal vein). Third region (highlighted in red). No. 13: Retropancreatic. No. 14: Superior mesenteric artery and vein, divided into No. 14v (venous), No. 14a (arterial). No. 15: Middle colic artery. No. 16: Paraaortic divided into No. 16a1 (hiatus of the esophagus), No. 16a2 (from the celiac trunk to the renal vein), No. 16b1 (from the renal vein to the inferior mesenteric artery), No. 16b2 (from the inferior mesenteric artery to the aortic bifurcation). No. 17: On the anterior surface of the pancreatic head beneath the pancreatic sheath. No. 18: Along the inferior border of the pancreatic body. No. 19: Infradiaphragmatic predominantly along the subphrenic artery. No. 20: Paraesophageal in the diaphragmatic esophageal hiatus. No. 110: Paraesophageal in the lower thorax. No. 111: Supradiaphragmatic separate from the esophagus.

Figure 2 N1, N2, and N3 lymph node stations in distal gastric cancer. A: N1 stations in red; B: N2 stations in yellow; C: N3 stations in green.

Table 1 Incidence of lymph node metastasis and index of estimated benefit from lymph node dissection in each station in lower third gastric cancer[86,87].

Lymph node station	Incidence of metastasis	Index of estimated benefit
1	6.2	1.6
2	7.1	0
3	40.9	17.3
4	34.2	14.5
5	10.5	3.9
6	46.3	21.3
7	23.4	8.2
8	24.5	7.5
9	12.8	3.9
10	3.8	0
11	6.7	1.0
12	9.0	2.7
13	8.3	0
14	14.6	2.1
16	13.1	2.4

It is important to emphasize that the N1 to N4 classification in the Japanese staging system is not comparable to the N0 to N3 definitions in the TNM system[21]. In the TNM classification, N0 identifies the absence of lymph node metastases, N1 identifies metastases in 1-6 regional lymph nodes, N2 in 7 to 15 lymph nodes, and N3 identifies metastases in more than 15 regional lymph nodes[8]. In the Japanese staging system, the invasion of the N3 lymph nodes and lymph nodes elsewhere in the abdominal cavity is defined as distant metastasis (M1).

Anatomy and regularity of lymphatic drainage

The anatomical studies of the lymphatic system conducted by Rouvière[22], subsequently confirmed and completed by other authors[23-25], highlighted three main groups of lymphatic vessels draining the stomach: (1) The left gastric artery, which drains the upper half of the lesser curvature; (2) The splenic artery, which drains the left half of the body and fundus; and (3) The hepatic artery, which supplies lymphatics from the antrum and the lower half of the greater curvature.

The Japanese Classification of Gastric Carcinoma subdivides the stomach into 3 regions (the upper, the middle, and the lower one), each with a different lymph drainage, and classifies regional gastric lymph nodes into separate stations. These stations include both peri-gastric lymph nodes, situated along the vessels that feed the stomach, and lymph nodes along major vessels and adjacent to the pancreas, the diaphragm, and esophageal hiatus[26].

The celiac lymph nodes form three main groups: Gastric, hepatic, and spleno-pancreatic. The gastric lymph nodes include the left gastric, right gastroepiploic, and pyloric groups (Nos. from 1 to 7). They receive their afferent lymphatics from the stomach and the abdominal portion of the esophagus. Efferent lymphatics drain to the celiac group of preaortic lymph nodes. The right gastroepiploic lymph nodes are in the greater omentum along the pyloric half of the greater curvature; they receive afferent lymphatics from the stomach; their efferent lymphatics mainly reach the pyloric lymph nodes. Four or five pyloric lymph nodes are located near the bifurcation of the gastroduodenal artery, in the angle between the superior and descending portions of the duodenum. A peripheral lymph node of this group is sometimes located above the duodenum, near the right gastric artery. They receive afferent lymphatics from the pyloric portion of the stomach, the first portion of the duodenum, and the right gastroepiploic lymph nodes. The hepatic lymph nodes are distributed in the lesser omentum along the hepatic arteries and the common bile duct and vary in number and location. The spleno-pancreatic lymph nodes (Nos. 10, 11 and 13) accompany the splenic artery near the posterior surface and superior margin of the pancreas; one or two lymph nodes of this group are in the gastrolienal ligament. Their afferent blood comes from the stomach, spleen, and pancreas; the efferent blood reaches the celiac lymph nodes.

In tumors of the lower third of the stomach, 3 main lymphatic flow pathways are present[27]. The first route concerns tumors located along the lesser curvature, where flow from the lesser curvature and supra-pyloric lymph nodes (Nos. 3 and 5) flows to the left gastric node (No. 7) and from there, through the tripod node (No. 9), reaches the para-aortic lymph nodes (Figure 3A). The second route (Figure 3B) concerns tumors located along the greater curvature, where flow from the peri-gastric lymph nodes along the greater curvature (No. 4d) and infra-pyloric nodes (No. 6) flows to the hepatic artery lymph nodes (No. 8a) and then reaches the para-aortic lymph nodes (No. 16b1). A third diffusion route (Figure 3C) has been identified, which flows directly from the infra-pyloric lymph nodes (No. 6) to the para-aortic lymph nodes (No. 16b1) through the mesenteric artery and vein (No. 14). Further classifications of lymphatic flows have been proposed[28]. The lymphatic compartments are divided into five directions that follow the main arteries of the stomach. According to this approach, lymph flows follow the left gastric artery, the right gastric artery, the right and left gastroepiploic arteries, and the posterior gastric artery. This would therefore determine three prevalent lymph flow routes for distal gastric cancer: Left gastric artery (Nos. 3a, 1, and 7), right gastric artery (Nos. 3b, 5, and 8a), and right-gastroepiploic artery (Nos. 4d and 6).

Figure 3 Lymphatic pathways in distal gastric tumors. A: Blue shows lymph node stations in tumors located along the lesser curvature; B: Red shows lymph flow in tumors located along the greater curvature; C: Yellow shows lymph node stations involved in tumors of the distal portion of the greater curvature and the pyloric region[27].

ARE 16 ENOUGH? IS THIS ANOTHER PROBLEM?

Optimal lymph node retrieval

It is well documented that lymph node involvement is a critical prognostic factor in gastric cancer[29]. Lymph node metastases are also present in T1b patients and in over 50% of patients with T2 tumors[30]. However, the results of several studies suggest that the evaluation of 16 lymph nodes in gastric cancer may be inadequate both for the accuracy of nodal staging and for improving patient survival.

Macalindong et al[31] found that the 5-year disease-free survival rate was not significantly different between the lymph nodes < 30, lymph nodes 30-45, and lymph nodes > 45 groups (72.9% vs 79.2% vs 76.2%, respectively, P = 0.5) in stage II patients. Vuong et al[32] also found that salvaging 30 or more lymph nodes resulted in a benefit only for patients with pT1N3 and pT2N3 gastric cancer. Other studies have attempted to identify a node threshold for theoretical oncologic benefit and survival advantage. Mirkin et al[33] have investigated 1036 pathological N0 patients with gastric cancer who received neoadjuvant therapy and found a survival benefit with 30 nodes examined. In addition, Brenkman et al[34] evaluated a Dutch cohort and showed that high number of lymph nodes was associated with prolonged survival in elderly patients. Recently, removal of 30 lymph nodes has been recommended for more accurate staging, with benefits for long-term survival[35]. Analysis of the Surveillance, Epidemiology, and End Results database (13932 patients) and gastric cancer patients at Yonsei University (11358 patients) showed that the greatest survival benefit was derived from examining additional lymph nodes beyond 15, up to 29 lymph nodes. The cutoff of 29 lymph nodes remained significant even after stratification by disease stage (hazard ratio = 0.799, P < 0.001)[36]. An optimal cutoff of > 20 lymph nodes were identified by analysis of the National Cancer Database results. Improved 3- and 5-year survival (hazard ratio = 0.80, P < 0.001) was documented especially in patients with 20-29 lymph nodes removed[37]. Hayashi et al[38] recommended the retrieval of more than 40 lymph nodes after total gastrectomy for stage III patients, whereas Lu et al[39] suggested that harvesting 21 lymph nodes might represent a superior cut-off point for radical gastrectomy to better determine the prognosis of the patients. The multicenter study conducted by Zhang et al[2] analyzed a population of over 2000 patients with gastric cancer who underwent gastrectomy after neoadjuvant treatments. The study demonstrated that a greater number of retrieved lymph nodes is associated with an improvement in overall survival and disease-specific survival. Although neoadjuvant therapy has the potential to reduce positive nodes burden, the authors identified 24 as the minimum number of retrieved lymph nodes.

At the same time, although a greater number of removed lymph nodes is associated with more appropriate staging and improved long-term survival, the perioperative risk of complications may significantly increase in patients undergoing extensive lymphadenectomies (> 30 lymph nodes removed)[40,41]. The Italian Research Group for Gastric Cancer, based on data collected from a prospective database of 2822 patients treated in high-volume centers (78% and 53% of cases with more than 15 and 25 removed nodes, respectively), highlighted that overall postoperative mortality was 3.5%, even when including aged patients or advanced stages[42]. Additionally, an analysis of 40281 patients, included in the American National Cancer Database for gastric cancer, showed a higher 30-day mortality (4.3%) after > 29 lymph nodes were removed compared to a resection of 15-28 nodes and < 15 nodes (3.0% and 2.1%, respectively)[43]. A higher incidence of surgical complications was observed in the patient group with more than 35 lymph nodes retrieved (15.5%) compared to patients in which fewer lymph nodes were removed (1.2%, P = 0.0005). On multivariate analysis lymphadenectomy with retrieval of more than 35 lymph nodes correlates significantly with the rate of surgical complications (P = 0.001)[40]. A recent study documented that in patients undergoing D2 lymphadenectomy, the incidence of delayed gastric emptying is double that of patients undergoing D1 lymphadenectomy (32% vs 15.4%). More extensive lymphadenectomy is directly associated with an increased risk of developing delayed gastric emptying in the postoperative period, on multivariate analysis (odds ratio = 3.63, 95% confidence interval: 1.12-11.8, P = 0.03)[44].

It should be assumed that a significantly greater number of lymph nodes is removed when an appropriate D2 lymphadenectomy is performed. It therefore seems likely that in patients with gastric cancer D2 lymphadenectomy allows removal of many more lymph nodes than 16, especially if pathological analysis of the surgical specimen is performed at high-volume centers. Practices that ensure adequate lymph node evaluation by pathologists include intraoperative lymph node labeling and back-table dissection with separation of nodal stations, which have been shown to increase the number of pathologically evaluated lymph nodes. Moreover, it is important to note that the extent of lymphadenectomy is directly related to the number of lymph nodes retrieved. A cadaver analysis demonstrated that complete nodal clearance from the D2 nodal stations should result in an average of 29 lymph nodes in distal gastrectomy and 31 lymph nodes in total gastrectomy. A mean of 33 lymph nodes in D2 lymphadenectomy in gastric cancer-free individuals has been identified[45]. Furthermore, studies of surgical dissections have shown that in patients with distal gastric cancer undergoing D1 lymphadenectomy, a mean of 26 lymph nodes (range 8-55) were removed and in patients undergoing D2 a mean of 37.4 lymph nodes (15-72)[46]. It has been shown that the number of lymph nodes found in each station is variable and many stations do not contain lymph nodes despite adequate resection and thorough pathological examination.

An evaluation based exclusively on the number of lymph nodes removed may be incomplete and, above all, compromise the therapeutic role of lymphadenectomy in cases of advanced gastric cancer. In evaluating the number of lymph nodes in the stations grouped by compartments, it has been documented that the number of 16 lymph nodes is easily reached even by removing only the peri-gastric stations[47].

Quality control of lymphadenectomy

Several studies have shown that hospital volume had a positive association with surgical outcomes for patients with gastric cancer. Mahar et al[48] reported a systematic review of the effect of the surgeon-institution factor on surgical outcomes for gastric cancer. They reported that the surgeon-institution factor influenced outcomes for patients undergoing gastrectomy. A high volume of patients admitted for the procedure was associated with low procedure-related mortality. Iwatsuki et al[49] studied national data from Japan and reported that the volume of patients admitted has a crucial impact on postoperative morbidity and mortality after distal gastrectomy. The operative mortality rate was 1.9% in low-volume hospitals and decreased to 0.5% in high-volume hospitals (P < 0.001). These findings suggest that centralization may improve outcomes for patients undergoing gastrectomy. Indeed, several studies have confirmed the positive influence of surgeon specialization on survival after gastrectomy. Patients operated on by surgeons performing fewer than two gastrectomy procedures per year were associated with a higher frequency of distant metastases or peritoneal spread. Surgeon status is a significant predictor of morbidity and mortality after gastrectomy for gastric cancer[14,49-51].

The optimal extent of lymphadenectomy in radical surgery for patients with gastric cancer has long been debated in Europe. The most recent European guidelines recommend performing a D2 lymphadenectomy in specialized centers[18,52-54]. Compliance with these guidelines is unclear. It seems necessary, however, to define surgical compliance[55,56]. Noncompliance can be defined as failure to remove planned lymph nodes. Contamination would indicate the removal of lymph nodes that should not have been removed[55]. This aspect is significant and has influenced several important multicenter studies. D2 non-compliance primarily involves the removal of lymph node stations Nos. 10, 11d, and 12a in total gastrectomy and stations Nos. 4sb, 11p, and 12a in subtotal gastric dissection. Contamination often involves the removal of stations Nos. 8p, 12b, and 12p in total gastrectomy and of stations Nos. 8p, 11d, 12b, and 12p in subtotal gastrectomy[14]. In the Dutch Gastric Cancer Trial[57], noncompliance was highest in the group of patients undergoing D2 lymphadenectomy (25.9%). The CRITICS study[58] documented pathological compliance (≥ 15 lymph nodes) in 72.8% of cases, with an improvement from 55% to 90% over time. Surgical compliance (adequate nodes) was documented in 41%, with an incidence of contamination of up to 59.6%. In the LOGICA study[59], intraoperative photographic assessment was used to verify correct dissection. The results of the study documented histological compliance in 38% of cases, mild non-compliance in 46%, severe non-compliance and contamination in 8% of cases.

To address noncompliance and contamination, the Korean multicenter observational study KLASS-02-QC[60] planned to standardize the anatomical definition of the D2 stations, in order to qualify the surgeons participating in the trial through specific training. Furthermore, a recent survey[61] conducted in Italy revealed several discrepancies between surgeons’ self-reported attitudes and data from patient clinical reports. The survey results revealed that adherence to guidelines was not always rigorous. A quality control program for lymphadenectomy for distal gastric cancer should include the minimum goal of removing ≥ 16 lymph nodes and the ideal goal of removing approximately 30 lymph nodes.

BEYOND D2 LYMPHADENECTOMY IN DISTAL GASTRIC CANCER

Unfortunately, there are discrepancies in the major international guidelines regarding the lymph nodes to be removed in the surgical approach to distal gastric cancer. Japanese guidelines establish the standard treatment for gastric cancer based on tumor stage[17]. The Japanese Gastric Cancer Association has defined the type of dissection based on the type of gastrectomy (Table 2). The Chinese Society of Clinical Oncology guidelines recommend D2 lymphadenectomy as described by Japanese guidelines in cases of distal gastric cancer, advising the removal of > 16 lymph nodes for appropriate staging[62]. In Brazil, a D2 lymphadenectomy with at least 25 harvested lymph nodes is recommended[63]. The guidelines of the European Society for Medical Oncology[64,65] and the National Comprehensive Cancer Network[66,67] are not as timely and precise as the Japanese guidelines (Table 3). Western guidelines do not clearly define the relationship between the type of gastrectomy and the extent of lymph node dissection. In these guidelines, stations No. 12a and No. 10 are not specifically mentioned[68,69]. The Italian group follows the guidelines of Japanese Gastric Cancer Association for indications, surgical procedures, and classification of lymphadenectomy. As in Japan, D2 is the standard treatment in Italy for potentially curative resection, even after neoadjuvant therapy. According to Italian guidelines, D2 plus with lymphadenectomy of the posterior stations (Nos. 8p, 12p/b, 13), station No. 14v, and additional removal of the para-aortic lymph nodes (Nos. 16a2, 16b1), is justified in patients at high risk of metastasis in these stations (advanced tumors and diffuse histology located in the distal two-thirds of the stomach)[70]. However, these procedures should be performed in high-volume centers.

Table 2 Extent of systematic lymphadenectomy according to the type of gastrectomy indicated[17].

Lymphadenectomy	Gastrectomy
	Total	Distal
D1	Lymph node stations Nos. 1, 2, 3, 4, 5, 6, and 7	Lymph node stations Nos. 1, 3, 4sb, 4d, 5, 6 and 7
D1+	D1 stations plus stations Nos. 8a, 9, and 11p	D1 stations plus stations Nos. 8a, and 9
D2	D1 stations plus stations Nos. 8a, 9, 10, 11p, 11d, and 12a	D1 stations plus stations Nos. 8a, 9, 11p, and 12a

Table 3 Lymph node groups to be resected for D1 and D2 lymphadenectomy according to clinical practice guidelines.

Ref.		D1 lymphadenectomy	D2 lymphadenectomy	Type of gastrectomy
[68]	NCCN	Stations Nos. 1, 2, 3, 4, 5, 6	Stations Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11	Not specified
[66]	ESMO	Stations Nos. 1, 2, 3, 4, 5, 6, 7	Stations Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 11	Not specified
[17]	JGCA	Stations Nos. 1, 2, 3, 4, 5, 6, 7	Stations Nos. 1, 2, 3, 4, 5, 6, 7, 8a, 9, 10, 11p, 11d, 12	Total
		Stations Nos. 1, 3, 4sb, 4d, 5, 6, 7	Stations Nos. 1, 3, 4sb, 4d, 5, 6, 7, 8a, 9, 11p, 12a	Distal
[69]	Polish Consensus	Stations Nos. 1, 2, 3, 4, 5, 6, 7	Stations Nos. 1, 2, 3, 4, 5, 6, 7, 8a, 9, 11, 12a	Total
		Stations Nos. 1, 3, 4sb, 4d, 5, 6, 7	Stations Nos. 1, 3, 4sb, 4d, 5, 6, 7, 8a, 9, 11, 12a	Distal
[70]	Brazilian Group	Stations Nos. 1, 2, 3, 4, 5, 6	Stations Nos. 1, 2, 3, 4, 5, 6, 7, 8a, 9, 10, 11p, 11d	Not specified

NCCN: National Comprehensive Cancer Network; ESMO: European Society of Medical Oncology; JGCA: Japanese Gastric Cancer Association.

D2 plus station No. 14v

In the 2^nd English edition of the Japanese Classification of Gastric Cancer[71], lymph nodes No. 14v are defined as regional lymph nodes in distal gastric cancer. More specifically, station No. 14v is considered part of the second group/compartment of lymph nodes in distal gastric cancer. Lymphadenectomy of this station is recommended during D2 lymphadenectomy for distal gastric cancer. The basis for this recommendation was that this classification grouped lymph nodes based on the results of studies of lymphatic flow at various tumor sites, along with the observed survival associated with metastases in each nodal station. These assumptions and the observation that tumor site influences the location of lymph node metastases are further exemplified in the 3^rd English edition of the Japanese Classification of gastric carcinoma[72], which continues to include lymph node 14v among the regional lymph nodes of gastric cancer, along with stations 1-12. However, the Japanese Gastric Cancer Treatment guidelines 2010 (version 3)[73] do not include station 14v in D2 lymphadenectomy for either total or distal gastrectomy. It is reported that the role of No. 14v lymphadenectomy in distal gastric cancer is controversial. Dissection of node No. 14v had been a part of D2 gastrectomy defined by the previous edition of the Japanese classification, but it has been excluded from more recent editions. Similarly, the 6^th edition of the Japanese Gastric Cancer Treatment guidelines[17] does not mention station No. 14v among the lymph nodes that should be removed during an appropriate D2 lymphadenectomy. Station No. 14v dissection is included among the D2+ lymphadenectomies, considering it necessary for distal gastric cancers with metastases to station No. 6 lymph nodes[17].

The incidence of metastases at lymph node No. 14v is not negligible. Literature reports show an incidence of metastasis at this site ranging from 4.3% to 18.5% in patients with distal gastric cancer[74-79]. Another study found that the incidence of metastasis at lymph node site No. 14v was 12.1% in the entire patient population examined, 1.3% in early gastric cancer, and 19.7% in advanced gastric cancer[74,80].

In distal gastric cancer, metastatic involvement of lymph node No. 6 can predict the status of metastasis at lymph node No. 14v[81]. Metastasis at lymph node No. 6 has proven to be a useful predictor of metastasis at lymph node No. 14v, with high accuracy (99.0%) and a low false-negative rate (1.9%). It should be noted that the incidence of lymph node metastases in lymph node No. 14v is < 1% in T1 patients, while it increases to 5%-10% in T2 or more advanced patients. Furthermore, metastatic involvement of lymph node No. 14v is directly related to the patient’s N+ stage; while no metastases in lymph node No. 14v have been documented in N1 patients, the incidence was 5% in N2 patients and 19% in N3 patients. The presence of metastases in lymph nodes No. 6 and No. 11p may indicate the need for No. 14v dissection[81]. Furthermore, the incidence of lymph node metastasis in stage II, IIIa, IIIb, and IIIc was 1.6%, 6.3%, 20.5%, and 32.2%, respectively, and increased to 66.7% in stage IV[79]. Metastasis to lymph node No. 14v was found to correlate significantly with tumor location (region including the lower third of the stomach) and depth of invasion (muscularis propria or deeper). Clinical findings suggest that lower gastric cancer with serous invasion or metastasis to lymph node No. 6 had a higher rate of metastasis to lymph node No. 14v.

The prognostic role of lymph node dissection of No. 14v lymph node in gastric cancer is controversial. In some studies, survival in patients with metastases to No. 14v lymph node, even after curative resection, is comparable to that of patients with M1 disease[75]. Conversely, No. 14v lymph node dissection has been shown to improve overall survival in patients with distal gastric cancer, primarily in patients with clinical stage III/IV distal gastric cancer[78,81-84].

To summarize, evidence supports the need to extend lymph node dissection to No. 14v lymph nodes in patients with distal gastric cancer[19,84,85]. First, the incidence of metastases to the No. 14v lymph node in stage III disease is relatively high. Secondly, lymphadenectomy of node No. 14v reduces the incidence of local residual tumor and increases the likelihood of curable resection, improving overall survival. Third, lymphadenectomy of nodes No. 14v would make nodes No. 6 dissection more complete in cases with metastatic involvement at this site.

D2 plus station No. 13

The prognostic value of lymphadenectomy at this level has been debated for years. However, results from several studies have gradually reassessed its relevance, particularly in cases of advanced gastric cancers located in the distal third of the stomach or in the presence of duodenal invasion. Among the earliest studies on the topic, Maruyama et al[86] analyzed 1931 cases of advanced gastric cancer, showing that station No. 13 was infrequently involved by tumor spread. When metastasis was present, the 5-year survival rate did not exceed 6%. However, in distal gastric cancers, metastasis to station No. 13 was observed in up to 58% of cases, and a correlation was noted with the involvement of the station No. 6.

Once this correlation has been established, in order to quantify the expected benefit of removing a specific lymph node station, and thereby assess its clinical relevance, Sasako et al[87] proposed a “therapeutic index” for lymphadenectomy, calculated by multiplying the incidence of metastasis at a given station by the 5-year survival rate of patients with metastasis at that site. For station No. 13, the index was initially considered not clinically significant. Nonetheless, its involvement was confirmed to be associated with distal and more extensive tumors (involving more than two-thirds of the stomach), highlighting the importance of tailoring the extent of lymph node dissection based on tumor location to avoid unnecessary surgical maneuvers. As a result of these early findings, station No. 13 was classified as N3 or M according to the 2^nd edition of the Japanese Classification of Gastric Carcinoma. However, in 2009, Tokunaga et al[88] analyzed data from 395 patients with distal gastric cancer, distinguishing between those with and without duodenal invasion. In patients with duodenal involvement, the therapeutic index for station No. 13 reached 4.19%, comparable to that of stations included in a standard D2 lymphadenectomy (stations Nos. 7, 9, 11p, and 12a).

Based on these findings and in accordance with both the TNM classification and the 15^th edition of the Japanese Classification of Gastric Carcinoma, starting from the 3^rd edition of the Japanese Gastric Cancer Association guidelines, station No. 13, although still formally classified as M, may have a potential curative role if removed in selected cases. In the 5^th edition, it is stated that station No. 13 should be considered a regional lymph node in the presence of duodenal invasion. This conclusion is supported by Kumagai et al[84], who argued that certain lymph node stations should be categorized as regional based on the TNM principle that regional lymph nodes include those of all involved sites if a tumor involves more than one site[89]. Analyzing a retrospective cohort of patients with distal-third gastric cancer and duodenal invasion operated on between 2000 and 2015, the study reported a 26.7% incidence of metastasis to station No. 13, a 5-year survival rate of 25.4%, and a therapeutic value index of 6.8%. Interestingly, a retrospective analysis of 528 patients from the Korean National Cancer Center with tumors invading at least the muscularis propria and located in the mid-to-distal stomach, showed that resection of station No. 13 was associated with significantly better survival in patients with stage III or IV disease. No survival benefit was observed in patients with stage I or II disease[90]. Similarly, Liang et al[76] evaluated the role of extended D2 lymphadenectomy including station No. 13 (“D2 plus” = D2 plus Nos. 12b, 12p, 13, and 14v) in patients with distal-third gastric cancer and serosal invasion. While the therapeutic values reported for station No. 13 were lower than in Kumagai’s study, the presence of metastasis in station No. 13 correlated with a 5-year survival rate of 42.9%. Overall, the D2 plus group showed a significantly higher 5-year overall survival rate (55.3% vs 43.9%) and a lower recurrence rate (51.5% vs 69.5%) then the D2 after matching adjusting the covariates. Furthermore, at the multivariate analysis extent of lymphadenectomy remained an independent prognostic factor.

Further supporting the role of station No. 13 lymphadenectomy, two prospective randomized studies were published in 2019. In the first, 64 patients with advanced distal gastric cancer were enrolled and randomized to D2 or D2 plus groups. The metastasis rate at lymph node station No. 13 was 9.4%, significantly associated with duodenal invasion. Considering the subgroup analysis related to patients with duodenal involvement who underwent D2 plus, the 3-year disease-free survival is significantly better than that of D2 group (61.5% vs 20%)[85]. The second study confirmed the therapeutic value of lymphadenectomy at station No. 13 in cases of gastric cancer with pyloric infiltration, reporting a metastasis rate to station No. 13 of 18.8% and a therapeutic index of 10.9% (even if the overall survival was calculated on three years). Notably, survival rates were comparable between patients with and without metastasis to station No. 13, suggesting a survival benefit from resection even in the presence of nodal involvement[91]. To date, the importance of station No. 13 remains a relevant and evolving topic. Currently, only Japanese and Chinese guidelines consider lymphadenectomy at this level a therapeutic option in cases of duodenal invasion. In contrast, Korean, European, and United States guidelines do not yet recommend D2 plus as a standard approach.

CURRENT STATE AND FUTURE DEVELOPMENTS

Japanese guidelines have long provided detailed definitions of the extent of lymph nodes dissection, which have been adopted globally. Distal o total gastrectomy with associated D2 lymphadenectomy is considered the standard surgical procedure for potentially curable T2-4 gastric cancers, as well as for cT1N+ tumors[14,18,53]. While some guidelines follow the recommendations of the Japanese ones, others, such as the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines, do not provide such specific recommendations.

The extent of lymphadenectomy is a controversial issue in the surgical treatment of gastric cancer. Multiple studies have confirmed that lymph nodes located in the hepatoduodenal ligament (including 12a, 12b, and 12p), posterior to the pancreatic head, or at the root of the superior mesenteric vein, are often involved in distal gastric cancer with serosal invasion[75,88,92]. The Japanese guidelines consider the possibility of extending the lymph node dissection to other lymph node stations, although they define extended lymphadenectomy beyond D2 as a non-standard surgical procedure[17].

Many studies focus exclusively on the number of retrieved and metastatic lymph nodes, without adequately considering the anatomical location of the lymph node stations[93,94]. However, the anatomical location of metastatic lymph nodes is an important factor, especially in N1-N2 gastric cancers[95]. Furthermore, it has been suggested that the required extent of lymph node dissection may vary from patient to patient since the pattern of lymph node metastasis may depend on the tumor location[47,96-98]. The lymphatic flow is regular and directly related to the site of the tumor. Indeed, knowledge of the location of the primary tumor should suggest performing a personalized lymphadenectomy in small T1 tumors, considering the absence of involvement of the second-level lymph nodes. In a recent study, it was demonstrated that in T1b patients, the location of the primary tumor in the lower third of the stomach was associated with a higher number of lymph node metastases (2.1 ± 0.9) compared to T1b tumors in the middle third (1.4 ± 0.8, P = 0.001)[4]. Location in the lower third of the stomach was a risk factor for lymph node metastasis in early gastric cancer (odds ratio = 0.062, P = 0.02)[4]. Conversely, in advanced gastric cancer, both circular and longitudinal localization should be considered to focus the lymphadenectomy on the most frequently involved individual nodes. This allows, in selected cases, the nodal dissection to extend to nodes not typically included in a D2 lymphadenectomy[47].

The station 6 is considered an important confluence of lymphatic channels that drain the distal two-third of the stomach[99]. Metastasis to the station 6 is very common[100] and directly related to tumor size and its location[101]. It has been demonstrated that station 4d and 6 metastases were independently associated with 14v metastasis[78]. In fact, the guideline emphasizes that D2 lymphadenectomy plus 14v dissection may be beneficial for patients who are suspected to harbor metastasis to the station 6[73]. This recommendation is based on studies demonstrating improved overall survival in patients with stage III or IV lower gastric cancer undergoing this procedure[82]. Station No. 13 has been reported to be involved in distal gastric cancer with duodenal invasion. In cases where the tumor invades the duodenum, Chinese guidelines[62] follow the Japanese recommendations. This recommendation is based on evidence indicating a 26.7% rate of metastasis to station No. 13 in such cases[90,102]. The National Comprehensive Cancer Network and European Society for Medical Oncology guidelines do not provide such specific recommendations.

Other studies have shown that the rate of lymph node metastasis in lymph nodes No. 12p and No. 12b was 9.2% and 3.1%, respectively, and even after curative resection, the 5-year overall survival rate is significantly lower for gastric cancer patients with lymph node metastasis in lymph nodes No. 12b or No. 12p compared to those without (13.3% vs 35.1%, P = 0.02). Reports in the literature have focused on a single lymph node station such as Nos. 12b, 12p, 14v, or lymph node No. 13, and the prognostic value of dissection of multiple lymph node stations beyond the D2 nodes in the treatment of advanced distal gastric cancer has rarely been evaluated. Liang et al[76] demonstrated in a sample of 394 patients with distal gastric cancer with clinical serosal invasion that patients who underwent “D2 plus” lymphadenectomy had a significantly higher 5-year overall survival rate than those who underwent standard D2 (55.3% vs 43.9%, P = 0.04). In this setting, “D2 plus” lymphadenectomy removes a greater number of lymph nodes than standard D2 lymphadenectomy. The greater number of removed lymph nodes contributes to more adequate staging and improves long-term survival[32,39]. The advantage of the study by Liang et al[76] is that it focused on the common therapeutic value of simultaneous dissection of all these lymph node sites, rather than on a single station.

An approach similar to that used by Siewert and Stein[103] for tumors of the esophagogastric junction should also be adopted in distal gastric cancer, especially in the peripyloric region. Indeed, it has been documented that the main lymphatic pathways from the lower esophagus advance cephalad into the mediastinum along the celiac axis, while those originating from the cardia and the preferably flow toward the celiac axis, the splenic hilum, and the para-aortic lymph nodes[104]. Therefore, a different pattern of lymphatic spread is observed depending on the location of the tumor. The Siewert classification is essential for determining the appropriate surgical approach. At the same time, it is important to note that the extent of lymph node dissection is determined based on the tumor’s location[3]. A nationwide retrospective study in Japan of small gastroesophageal junction tumors (diameter < 4 cm) documented that lymph nodes along the distal stomach were much less likely to metastasize, and their dissection seemed unlikely to be beneficial, suggesting that total gastrectomy for dissection of lymph nodes Nos. 4sa, 4sb, 4d, 5 and 6 was considered unnecessary for small Siewert type II cancer[105]. However, when the tumor diameter is greater than 6 cm, the frequency of metastases in distal gastric nodes is 10.7%[106]. In summary, it can be considered that dissection of stations No. 5 and No. 6 was useful for Siewert type III but not essential in Siewert II[107]. It seems appropriate, therefore, that a similar approach, especially regarding the extent of lymphadenectomy, be used for distal gastric tumors, particularly if in the juxta-pyloric location.

CONCLUSION

In conclusion, the extent of lymph node involvement continues to be one of the most important prognostic factors for gastric cancer survival. Resection of an adequate number of lymph nodes is essential to ensure accurate patient staging and optimal treatment. However, it appears necessary to consider the location of the primary tumor, which influences metastatic involvement in lymph node regions not included in standard D2 lymphadenectomy. A more extensive lymph node dissection, although current guidelines support a minimum of 16 lymph nodes for evaluation in gastric cancer patients, would allow lymph node sampling and pathological identification of more lymph nodes, limit the effects of stage migration and improve survival. It may be useful to adopt a similar subdivision for antroduodenal junction tumors, as was done with the Siewert classification for esophagogastric junction tumors.