Introduction

Remnant gastric cancer is defined as a malignancy that develops on the remnant gastric stump after partial gastrectomy due to gastric malignant or benign disease [1]. The incidence of remnant gastric cancer after peptic ulcer surgery appears to be decreasing due to improvements in anti-ulcer medications [2]. However, improved screening surveillance with endoscopy and prolongation of the survival of primary gastric cancer patients have increased the incidence of detection of remnant gastric cancer after primary gastric cancer surgery [3, 4].

One of the treatment of remnant gastric cancer is radical surgical resection [5, 6]. However, unlike primary gastric cancer surgery, the optimal range of lymph node dissection for remnant gastric cancer has not been fully established. Japanese guidelines recommend that regional lymph nodes of the stomach not resected during the initial surgery be dissected in advanced remnant gastric cancer. The clinical benefits of splenic hilar lymph node and mesojejunal lymph node dissection have not been established [7]. Interestingly, recent studies that evaluated the patterns of lymph node metastasis in patients with remnant gastric cancer found that meso-jejunal lymph node metastasis was common in patients who had undergone gastrojejunostomy (Billroth II or Roux-en Y) reconstruction during initial surgery [8, 9]. The index value used to predict the therapeutic benefit of dissection of meso-jejunal lymph nodes was 11.0 in patients in the nationwide registry of the Japanese Gastric Cancer Association of patients who had undergone a gastrectomy with gastrojejunostomy due to primary gastric cancer [8].

Adequate lymph node dissection is not defined for patients with remnant gastric cancer. Therefore, in this study, we evaluated the prognostic significance of the index value of meso-jejunal dissection to determine its survival benefits.

Materials and methods

Between September 1996 and October 2019, 391 patients were diagnosed with remnant gastric cancer (RGC) and underwent surgical treatment at Samsung Medical Center. Among them, those diagnosed with unresectable state of RGC received neoadjuvant treatment. Adjuvant chemotherapy was usually recommended after surgery except for patients with stage T1N0 or T2N0 cancers. The median follow-up period after the second surgery of these patients was 51 months (range 0–294 months).

Clinicopathologic characteristics including age, sex, histology of primary disease, first operation reconstruction method (Billroth I [gastroduodenostomy], Billroth II/Roux-en Y [gastrojejunostomy] or esophagogastrostomy), RGC type, second operation type (completion total gastrectomy, extended completion total gastrectomy, open biopsy or palliative gastrojejunostomy), recurrent tumor curability (R0, R1, or R2), recurrent tumor involvement of greater curvature, No. 10 lymph node dissection, splenectomy, meso-jejunal lymph node dissection, recurrent tumor size, recurrent tumor histology (differentiated or undifferentiated), and recurrent tumor pathologic stage (including depth of invasion, lymph node metastasis, distant metastasis) were ascertained from medical records.

Patients were categorized according to Kaminishi’s classification [10], which defines primary, residual, and recurrent RGCs according to the interval between the first and second operations, primary disease (benign or malignant), and location of the recurrent cancer (anastomosis or non-anastomosis site). Tumor histology was dichotomized as differentiated, which included papillary adenocarcinoma and well or moderately differentiated adenocarcinoma, or undifferentiated, which included poorly or undifferentiated adenocarcinoma, signet ring cell carcinoma, mucinous carcinoma, and other types. Pathologic stage was classified according to the eighth edition of the American Joint Committee on Cancer Classification [11].

The therapeutic value of mesojejunal lymph node dissection was evaluated using an index, which was first proposed by Sasako et al. [12]. This index is used to evaluate the therapeutic value of dissection of individual lymph node stations not only in gastric cancer surgery [13] but also in other solid organ cancer surgeries such as pancreatic cancer [14] or colorectal cancer [15]. The survival benefit gained by dissection of meso-jejunal lymph nodes was calculated by multiplying the frequency of metastasis at the meso-jejunal lymph node station and the 5-year overall survival rate of patients with metastasis at that station. When the metastatic rate or 5-year overall survival rate exceeded 10%, dissection was recommended. An index value of dissection greater than 1.0 was considered significant. This cut-off value exceeds the minimum value of the index in regional lymph nodes of primary advanced gastric cancer according to the Japanese Classification of Gastric Carcinomas, 13^th Edition [8, 12, 16].

We obtained survival data of the enrolled patients from updated medical records and the National Statistical Office in Korea. Because this research is a retrospective cohort study, the need for ethical approval and consent were waived by the approval from the Institutional Review Board of Samsung Medical Center, Seoul, Korea (SMC 2022-03-020-001).

Results

Clinicopathologic characteristics of the 391 patients with remnant gastric cancer who underwent surgery are shown in Table 1. At the time of the second operation due to remnant gastric cancer, 59.1% of patients were older than 60 years, and most patients were male (76.5%). Of the 391 patients, 79.3% had malignant primary disease. Reconstruction after primary surgery was mostly performed by gastroduodenostomy (Billroth I, 41.2%) or gastrojejunostomy (Billroth II or Roux-en Y 57.0%). During total gastrectomy, No.10 lymph node dissection was performed in 11.3% of patients, and splenectomy was performed in 23.8%. Among those who had Billroth II or Roux-en Y anastomosis after primary surgery (n = 223), meso-jejunal lymph node dissection was performed in 60 patients during their second operation (26.9%).

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Table 1. Clinicopathologic variables of 391 patients with remnant gastric cancer.

https://doi.org/10.1371/journal.pone.0285554.t001

Meso-jejunal lymph node metastasis was found in 21 patients (35%), and their clinicopathologic characteristics are listed in Table 2. In patients with meso-jejunal lymph node metastasis, depth of invasion was T3/T4 (p < 0.001). High N stage was significantly more frequent in these patients than the other patients (p < 0.001), and more advanced pathologic stage (p < 0.001) was observed in patients with meso-jejunal lymph node metastasis than in those without meso-jejunal lymph node metastasis.

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Table 2. Clinicopathologic variables of 60 patients who underwent meso-jejunal lymph node dissection during remnant gastric cancer surgery.

https://doi.org/10.1371/journal.pone.0285554.t002

We calculated the index of the estimated survival benefit of meso-jejunal lymph node dissection and our findings are presented in Table 3. Because there were no metastatic nodes in the T1 subgroup, the index value could not be calculated for this group. However, in the T2-T4 group, the index was 13.8. Index value for the T2-T4 subgroups was 28.6 in patients with a benign tumor (primary disease), 16.7 in those with a tumor in the greater curvature (tumor location), and 13.7 in those with an anastomotic tumor location. The index value in the malignant (primary disease) group was 0.0, as none of the six patients with metastatic lymph nodes were alive 5 years after their second operation.

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Table 3. Index value of the estimated benefit of meso-jejunal lymph node dissection.

https://doi.org/10.1371/journal.pone.0285554.t003

Five-year overall survival rates in patients with meso-jejunal lymph node metastasis and those without metastasis were 28.4% and 85.1%, respectively (log rank p < 0.001, Fig 1). In multivariate analysis (Table 4), meso-jejunal lymph node metastasis was a significant independent prognostic factor (hazard ratio 6.77, 95% confidence interval 2.21–20.79, p = 0.001).

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Fig 1. Five-year overall survival rates in patients with meso-jejunal lymph node metastasis and those without metastasis were 28.4% and 85.1%, respectively.

The difference between the survival curve was statistically significant (log rank p < 0.001). Stage IV patients or patients with R1 or R2 resection were excluded.

https://doi.org/10.1371/journal.pone.0285554.g001

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Table 4. Univariate and multivariate analyses of the overall survival of patients (n = 49) who underwent meso-jejunal lymph node dissection during surgery for remnant gastric cancer.

https://doi.org/10.1371/journal.pone.0285554.t004

Discussion

Among 391 patients diagnosed with remnant gastric cancer, 57% (223/391) of patients underwent Billroth II or Roux-en Y reconstruction after distal gastrectomy. During their second operation, meso-jejunal lymph node dissection was performed in 26.9% (60/223) and metastasis was found in 35% (21/60) of patients who had undergone lymph node dissection. Patients with metastasis at that station concomitantly had advanced remnant gastric cancer. The index value of the estimated survival benefit of meso-jejunal lymph node dissection was 13.8 in the T2-T4 groups. In addition, meso-jejunal lymph node metastasis was a significant independent prognostic factor in multivariate analysis of overall survival.

One of the treatment of remnant gastric cancer is radical surgical resection [5, 6]. However, optimal surgical treatments have not been fully established, in particular in the field of lymph node dissection [9]. Lymphatic flow and incidence of metastasis after initial gastrectomy for benign disease without lymph node dissection might be the same as for primary gastric cancer. Previous lymph node dissection for initial malignant disease can increase lymphatic flow from the remnant stomach to lymph nodes in the para-aortic, greater curvature, suprapancreatic, jejunal, and colonic mesentery regions [17]. A recent study showed that a different pattern of lymph node metastasis was associated with remnant gastric cancer compared to primary gastric cancer. The pattern of metastasis indicated that jejunal mesenteric lymph nodes should be specifically targeted for en bloc resection during completion total gastrectomy [18].

According to previous studies, lymph node involvement in the jejunal mesentery is a phenomenon peculiar to remnant gastric cancer after gastrojejunostomy, with a reported incidence ranging from 7.0% to 46.8% [19]. Due to its high incidence, meso-jejunal lymph nodes should be dissected in remnant gastric cancer patients who underwent gastrojejunostomy during their initial surgery. However, the clinical benefits of this dissection are uncertain, largely because of the poor prognosis of patients with metastasis at this station [7, 19].

In this study, remnant gastric cancer patients with meso-jejunal lymph node metastasis had a significantly worse prognosis than those without meso-jejunal lymph node metastasis. However, the index value suggested that dissection of this station might have therapeutic benefit [8, 12, 16]. The index value was introduced by Sasako et al [12]. This index is used to evaluate the therapeutic value of dissection of individual lymph node stations in cancer surgeries [13–15]. Similar results were found in our study. We found that 34.6% (17/49) of patients had meso-jejunal lymph node metastasis and that the 5-year overall survival rate of node positive patients was 28.4%. The calculated index value was 13.8. Thus, we recommend dissection of meso-jejunal lymph nodes in patient diagnosed with advanced (T2-T4) remnant gastric cancer. Metastatic meso-jejunal lymph nodes not detected preoperatively can be dissected intraoperatively and there may be a survival benefit after meso-jejunal lymph node dissection. In a retrospective study using data from the nationwide registry of Japan reported a high index for meso-jeunal lymph nodes in pT2-T4 remnant gastric cancer regardless of the nature of the initial disease (malignant 10.9, benign 17.0) [8]. Interestingly, in our study, the five-year survival of node positive patients who had initial gastrectomy due to malignant disease (n = 6) was 0.0.

Limitations of this retrospective study are as follows. First, although the total number of patients who underwent meso-jejunal lymph node dissection for remnant gastric cancer was comparable to that evaluated in other studies [20, 21], this number is still quite low; furthermore, our study was a single center study. To address these shortcomings, external validation of our results and multicenter collaborative data concerning the optimal extent of lymph node dissection, including dissection of the meso-jejunal lymph nodes, is needed. Second, information bias could have occurred when evaluating the medical reports of patients who had their first operation at another institution. Last, this study could not reflect the effect of the development of adjuvant treatment and surgical techniques that might affect patient prognosis during long-term follow-up and the time between surgeries.

In conclusion, the survival benefits of dissection were high for meso-jejunal lymph node dissection in patients with advanced remnant gastric cancer previously anastomosed with gastrojejunostomy. Based on the calculated therapeutic index, dissection of the meso-jejunal lymph node station can be recommended during completion total gastrectomy for advanced remnant gastric cancer. Patients with meso-jejunal lymph node metastasis, however, showed poor survival. Meso-jejunal lymph node may be considered differently from other regional lymph nodes in terms of prognostic significance in patients with remnant gastric cancer. This high-risk group may need thorough follow-up and long-term chemotherapy.

Supporting information

Acknowledgments

The first author would like to express her thank to Junhyun Ahn Pharm D, PhD, for sharing insight and pearls of wisdom during the conceptualization of this study.