nPTD classification: an updated classification of gastric cancer location for function preserving gastrectomy based on physiological lymphatic flow

Gastric cancer location is generally described based on the Japanese classification of gastric carcinoma [1, 2]. The longitudinal axis is divided into three areas: upper (U), middle (M), and lower (L). This is simply divided into three equal parts: the lesser curvature and greater curvature of the stomach. However, the most important aspect of gastric cancer curative surgery is the lymph node dissection [3, 4], and for surgical treatment, classifying tumor location using lymphatic flow is useful.

Previously, our group found a correlation between gastric cancer tumor location and lymphatic flow distribution and proposed the Proximal–Transitional–Distal (PTD) classification based on gastric cancer location and lymphatic flow (Fig. 1a) [5]. The PTD classification is derived from gastric cancer-specific lymphatic flow observation using the dye method of sentinel node biopsy. Presently, sentinel node biopsy is the most reliable diagnostic method to identify lymph node metastasis in early gastric cancer [6]. The PTD classification is better than UML classification because it provides proper lymph node dissection index and guides function-preserving gastrectomy for early gastric cancer, such as proximal and segmental gastrectomies [5, 7].

Subsequently, sentinel node biopsy is continued, and further lymphatic flow regularity is confirmed in early gastric cancer. Thus, the PTD classification was updated, and the nPTD classification, a more suitable clinical practice tool, was developed.

This is a retrospective study of gastric cancer patients who underwent sentinel node biopsy both at Kanazawa University Hospital from 1993 to 2008 and at Kanazawa Medical University Hospital from 2009 to 2020. The sentinel lymph node biopsy indication for gastric cancer is the presence of a type 0 single lesion gastric cancer ≤5 cm in the long axis, which is clinically node-negative (cN0), as diagnosed by preoperative computed tomography [5, 8, 9]. In this study, patients included were those with an observable lymphatic flow during sentinel node mapping, using the dye method, while patients with > 5 cm in the long axis or a pathologically invaded layer deeper than the subserosal layer, and those whose accurate lymphatic flow was not observed were excluded.

At Kanazawa University Hospital, mapping was performed using the blue dye or the radioisotope (RI) and dye combination methods, and at Kanazawa Medical University Hospital, mapping was performed mainly by using the indocyanine green (ICG) fluorescence method. In the blue dye or the RI and dye combination methods, 0.2 ml of 2% sulphan blue was injected endoscopically into the submucosal layer’s four points around the tumor using the endoscopic injection needle immediately before or during surgery. The lymphatic flow was observed after 15 min, and the lymphatic basin and sentinel nodes were detected and recorded. Lymph nodes stained blue were regarded as sentinel lymph nodes [8]. In the ICG fluorescence method, ICG diluted to 50 μg/mL was used as a tracer; 0.5 mL of the tracer was injected endoscopically into the submucosal layer’s four points around the tumor for mapping the day before surgery. A small amount of ICG administered was sensitized and detected using Photodynamic Eye (PDE Hamamatsu Photonics). The lymphatic basin (basin through which the ICG fluorescent lymphatic vessel flow) was identified and recorded. Lymph nodes with clear fluorescence when observed with PDE were regarded as sentinel nodes [9].

The lymphatic basin is a certain lymphatic area that drains directly from the primary focus and is specific for gastric cancer. According to the previous report, lymphatic basins were defined as follows: the proximal side was the stomach wall, and the distal side was the most distal dye-stained lymph node [5]. Sentinel nodes are found only within lymphatic basins, which are integrated into the five lymphatic areas shown in Fig. 1b, except for the lymphatic flow to the left paracardial lymph node (No. 2 lymph node, #2). As previously reported, each of these is called the lymphatic compartment and is classified into five basins: the left gastric artery basin (l-GA), right gastric artery basin (r-GA), left gastroepiploic artery basin (l-GEA), right gastroepiploic artery basin (r-GEA), and the posterior gastric artery basin (p-GA). Classifying the lymphatic flow to #2 is challenging because of the multidirectional flow to l-GA and No. 19 lymph node ahead and the lymphatic flow to p-GA nearby. Therefore, it was excluded from the lymphatic compartment classification and handled separately [5, 8].

The lymphatic basin distribution was tabulated for each gastric cancer location, and gastric lymphatic flow regularity was examined. The UML was classified according to the Japanese gastric carcinoma classification [1]. Since it is clinically difficult to determine the boundary between U and M, the lesions located at the boundary between U and M (UM and MU) were counted separately in this study. The PTD classification was based on a previous report [5]. The boundary between zones P and T is the line connecting the point of the watershed between the left and right gastroepiploic arteries and the inflow point of the first descending branch of the left gastric artery. An arc with a radius of 8 cm from the pylorus was defined as the boundary between zones T and D. All tumor regions were determined preoperatively based on UML classification. According to the PTD classification, tumor regions were determined retrospectively from the endoscopic findings and surgical records of cases from Kanazawa University Hospital and preoperatively for cases from Kanazawa Medical University Hospital. Furthermore, we attempted to improve the PTD classification based on the distribution of lymphatic flow. Gastric cancer has been described following the Japanese classification of gastric carcinoma [1].

The chi-square test was used to compare background factors. P-values < 0.05 were considered significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface of R (The R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version of R Commander [10].

This study was approved by the ethics committee of Kanazawa University Hospital and Kanazawa Medical University (Trial Number R093 (28/08/2009), M288 (25/02/2013)) and registered with the University Hospital Medical Information Network’s Clinical Trials Registry (trial number UMIN000010154 and UMIN000023828). ICG mapping was approved by the ethics committee of Kanazawa Medical University (Trial Number M404 (25/07/2016) and jRCTs041180006 https://​jrct.​niph.​go.​jp/​latest-detail/​jRCTs041180006).

This study was conducted following the Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided written informed consent for surgery and use of their data. Regarding data used for lymph node mapping, patients were allowed to opt out of the study at any time.

The study aimed to update the PTD classification, especially to review the P and T zones. When the PTD classification was first published in 2008, the regional lymph nodes and D-number were classified based on the UML classification at that time [11]. Subsequently, the guidelines were revised; however, lymphatic flow was not emphasized in the current Japanese guideline.

Lymph node dissection must be based on lymphatic flow. Thus, it is necessary to focus on lymph flow to reduce the extent of lymph node dissection from D1+ without compromising curability. The sentinel node is a node that directly receives lymphatic drainage from a primary tumor [12]. The results of a multicenter prospective study showed that the sentinel node concept is valid for early gastric cancer [6]. In intraoperative node-negative cases diagnosed through sentinel node biopsy, it is thought that minimal nodal dissection limited to the lymphatic basin can be performed without compromising curability [5, 9], and a large-scale clinical trial to verify this is currently underway [12]. In addition, ICG fluorescence mapping has shown good results as an alternative to combination mapping [9]. In the present study, the size of the lesions was limited to ≤5 cm on the long axis. It was difficult to omit dissection due to the widespread lymphatic flow in gastric cancer > 5 cm, and there was a concern that the dye method could not accurately cover the lymphatic flow in large lesions.

The limitation of the old PTD classification is its difficulty in identifying the P and T boundary preoperatively. Intraoperatively, it is possible to determine this from the distribution of gastroepiploic arteries; however, it is challenging to determine the location of the tumor since the tumor is inside the stomach.

We observed that tumors located in watersheds of the greater curvature have extensive lymphatic flow into the three basins of l-GA, l-GEA, and r-GEA, and limited surgery should be cautiously performed on them. Thus, the ‘n’ zone was newly defined. The center of the ‘n zone’ is the watershed of the left and right gastroepiploic arteries in the greater curvature. This watershed corresponds to the constriction of the greater curvature of the body; therefore, it is easy to determine using the barium meal study. It is sometimes difficult to make a judgment with a gastrointestinal endoscopy, but it is a region that looks like a horse’s saddle when observed from the esophagogastric junction under sufficient inflation of air. The ‘n’ zone coincides with pre-linitis plastic cancer’s predominant site [13]. In addition, the boundary point in the lesser curvature was changed to the upper one-third point following the settings of the U and M boundary. This was a change in clarity. Furthermore, tumors confined to the P zone’s lesser curvature had no lymphatic flow to l-GEA, and the P zone was divided into two. If the tumor is localized to the PL, lymph node dissection of the l-GEA may be omitted. It is unclear why PL does not show lymphatic flow to the greater curvature, unlike T or D, but this is probably because the fornix has a large volume for receptive relaxation and the stomach wall is thin, resulting in less lymphatic confluence than that of the body or antrum.

Based on these results, the appropriate resection and dissection range for cT1N0 patients according to the nPTD classification is shown in Fig. 3. Although sentinel node biopsy is required to diagnose node-negative cases since metastasis rarely spreads out of the basin in cT1N0 patients, the extent of nodal dissection can be limited to the lymphatic basins and dissection out of the basin is omitted without compromising cure [5‐9]. For tumors located in D, distal half gastrectomy with nodal dissection of l-GA, r-GA, and r-GEA would be appropriate. In addition, segmental gastrectomy with nodal dissection of l-GA and r-GEA would be sufficient for tumors located in T [14‐16]. If the tumor is located in the PG, a proximal gastrectomy would be considered appropriate [17]. However, if the tumor is localized within the PL, dissection of l-GEA can be omitted so that the resection area can be further reduced [18]. The reduction in the extent of resection area in proximal gastrectomy is of great significance to patients because it has been reported that a larger residual distal stomach is associated with less post-gastrectomy complaints [17]. As for curability, cancer recurrence after function-preserving gastrectomy is unlikely in patients diagnosed as node-negative pathologically. The problem in curability is when pathological nodal metastases are found postoperatively. Nevertheless, the lymphatic basin dissection is performed as a backup dissection; therefore, it is unlikely that all such patients will require additional dissection. The need for additional nodal dissection should be determined by considering the status of nodal metastases. However, despite standard lymph node dissection, five of 42 cases of lymph node metastasis in the present study had a recurrence. Adjuvant chemotherapy may be more useful than additional dissection. Conversely, for cancers located in the ‘n’ zone, nodal dissection of l-GA, l-GEA, and r-GEA is required, and, as a result, nearly-total gastrectomy is required. However, cT1N0 occupying the ‘n’ zone was rare, with only 3.8% of occurrence. Indeed, for gastric cancer deeper than cT2 and gastric cancer with cN+, either distal or total gastrectomy with D2 is usually required. In addition, even with cT1N0 tumors, lesions spanning more than one zone require both resection and dissection in a range that combines the extent of each resection and dissection area.

There were some limitations to this study. Since the nPTD classification was decided retrospectively, a prospective study will be necessary to validate this proposal. The optimal surgery for cT1N0 patients based on the nPTD classification may also be verified prospectively. The handling of the No. 9 lymph node (#9) is also unclear from our data. The frequency of metastasis in cT1N0 patients to #9 is reported to be low, and the therapeutic index is also low [19]. Although we excluded #9 from the node to be dissected in our study, it would be no problem to define #9 as the node to be dissected in all cases.

Based on this in vivo observation of lymphatic flow, we developed the nPTD classification. Sentinel node biopsy for early gastric cancer is very useful for distinguishing node-negative cases and applying local resection; however, it requires several resources, and there are still unsolved issues [18]. Until these issues, such as rapid intraoperative diagnosis and adequate surgical procedures, are resolved, the nPTD classification will play an important role in performing the function-preserving gastrectomy as an alternative to the sentinel node biopsy.