Prognostic significance of lymph node dissection on stage-specific survival for patients with primary small intestine tumor treated with enterectomy: A population-based study, 2004-2015


 Background: The positive rate of lymph node detection(LND) can be used as a predictor of prognosis for patients undergoing radical resection of small bowel tumors; thorough local LND may be crucial for the accurate staging and management of the disease.The purpose of our study was to determine the effect of the LND in specific stages. Methods: This study included 5413 patients with primary small intestine tumors after enterectomy within SEER database from 2004-2015. A multivariable COX model and Kaplan-Meier plots survival curves were used to analyze survival.Results: Of the 5413 patients, 4675(86.4%) underwent lymphadenectomy, and 3896(72.0%) were moved 4 or more than 4 lymph nodes. LND was performed in 67.8%, 83.3%, 87.9%, 89.3% in pT1/2/3/4 disease. In multivariable Cox regression analyses, LND was associated with OS and CSS, and the extended LND are better than limited LND (all P<0.05 except pT2). Kaplan-Meier plots survival curves showed that LND can benefit patients.Conclusions: The removal of LND with 4 or more lymph nodes in pT1/3/4 patients has relatively obvious benefits for survival. The effect of LND with more lymph nodes is significantly better than limited LND. For pT1, pT3 and pT4, LND can be considered.


Introduction
Primary malignant small intestine tumor is a very rare gastrointestinal tumor. Due to its rarity, we still do not know enough about small intestine tumors. The most frequent small bowel tumors are adenocarcinoma (30-40%), neuroendocrine tumors (35-44%), lymphomas (10-20%) and gastrointestinal stromal tumors (12-18%) [1][2][3] . Even with the advances in therapeutic methods, surgery is still the main method of curing small bowel tumor patients 4 .
Lymph node status is one of the most important prognostic indicators for solid organ malignancies. As tumors develop, they acquire increased genetic heterogeneity, which is associated with tumor progression and subsequent spread. In the AJCC Cancer Staging Manual (7th edition), the TNM classi cation places patients with regional lymph node metastasis (N1) in stage IIIB disease. Recently, several studies discussed the number of positive lymph node detections used to de ne the grade of lymph node metastasis in order to obtain a better survival prognosis [5][6][7][8] , which indicates that lymph node metastasis is a very important prognostic indicator of small intestinal tumors. It has been proved that for patients undergoing radical resection of small bowel tumors, the positive rate of lymph node detection can be used as a predictor of prognosis 7,9 . A study 10 believe it be used as a predictor of tumor recurrence and distant metastasis after curative surgery. Therefore, thorough local lymph node dissection may be crucial for the accurate staging and management of the disease 5,6 . However, lymph node dissection will still bring some controversy, a higher number of positive lymph node detections may be associated with a poorer prognosis 5 .
There is no precise conclusion as to whether ample bene ts can be obtained from lymph node dissection of various degrees. Although the reports of each stage model are separate, there is still a small amount of them about evaluation and comparison of the effect of LND in patients with small bowel cancer at different T stages. Therefore, We look forward to being able to further judge the role and the usage indicators of lymph node dissection to pursue greater bene ts. the purpose of this study is to evaluate the bene ts that different degrees of lymph node dissection can bring to patients with small bowel tumors, and to predict cancer speci c survival in each speci c-stage disease, based on a large population from the Surveillance, Epidemiology, and End Results(SEER) database. http://seer.cancer.gov/seerstat/ ). SEER provided population-based data about cancer incidence, feature, treatment and survival status throughout the country covered more than 34% population. We de ned the  Table 1).

Methods
The primary outcome in this study was a measure of cancer-speci c death, de ned as a death with the speci c cancer of interest listed as the primary cause of death in the SEER registries 11 .

Variables for analyses
Patients were strati ed according to presence or absence of LND. The covariables include age of diagnosis, gender(male, female), race(black, white, other),marital status(married , single , other ), grade( , ) tumor stage(T1, T2, T3, T4 ), lymph node stage(N0 , N1 , N2 , N3), metastasis(M0, M1), tumor size( 5cm , ≥5 cm) and year of surgery categories (2004-2007 , 2008-2011 , 2012-2015) Statistical Analysis A description and comparison of the baseline characteristics of the patients from the database (SEER) treated with lymph node dissection or no without lymph node dissection was conducted in which the concomitant variables were compared by the chi-square or Fisher's exact test, as appropriate. Kaplan-Meier plots survival curves and log rank tests were used to compare the overall survival (OS) and the cancer-special survival (CSS). First, Cox proportional hazards models were used to test the effect of the lymph node dissection in small intestine cancer surgery by comparing the LND and no LND group and assumptions of proportionality were veri ed. All statistical analyses were performed with SPSS version 24.0 (SPSS Inc, Chicago, IL, USA), GraphPad Prism 8.0.4 and R version 3.6.1 (http://www.r-project.org).
Statistical signi cance was set at two-sided P <0.05. The Kaplan-Meier method was used to estimate overall survival rate and cancer-special survival rate in the different stage and the differences were evaluated using the log-rank test with a threshold of P<0.05.
Comparing the covariables of LND and NO LND groups, we found that age, race, grade, T stage, N stage, Marital status and tumor size were predictive factors. Younger, non-white race, poorly differentiated, higher t-stage, lymph node metastasis, unmarried, and larger tumor size are the determinants of lymph node dissection. (Table 2) Survival analyses according to LND status The 3-year ,5-year and 10-year OS CSS rates for all T stages patients grouped by the different LND status were shown in Table 3. For the LND patients and no LND patients, the overall survival rate and cancerspecial survival rate were 51.1% vs 38.6% and 68.2% vs 61.4%. For LND and no LND patients, T stagespecial 5-year OS rates and CSS rates were as follow: pT1 were 76.2% vs 48.2% and 95.1% vs 78.3%, pT2 were 73.2% vs 64.7% and 89.3% vs 86.5%, pT3 were 54.3% vs 37.4% and 71.6% vs 65.7%, pT4 were 37.9% vs 23.2% and 53.6 v 52.7%.
According to the LND status, extended LND status and neuroendocrine adenoma status, we analyzed the hazard rates of the patients in special T stage. Compared to the patients treated with no LND, the patients who underwent LND had lower hazard rate for OS (HR=0.592, P=0.013), but not CSS (HR=0.981, P=0.809) ( Table 4, Table 5).Subdivided according to stage ,LND would provide bene ts in different stage except pT2 disease. Patients who accepted limited LND treatment had not enough bene t from LND in speci cstage disease except pT1(HR=0.516;P=0.012).By contrast, patients who treated by extended LND would bene ted more from lymph node dissection(HR=0.567;P=0.009) ,but not in pT2 stage(0.716;P=0.114).Similar results appear in the CSS analysis (Table 5).We only nd that patients with pT1 tumor could bene t from the limited LND when OS rates were tested(HR=0.516;P=0.012), and we didn't nd any other bene t from limited LND in both OS and CSS tests. Otherwise, the positive and protective effect could only be found in pT1 stage when the N-stage were compared for OS rates. Quite differently, when it comes to CSS rates, with the exception of pT1 and pT2 stage, patients with N0 stage could get more bene t from the extended LND (Table 5).

Discussion
Compared with colorectal cancer, the incidence of small bowel tumors is very low, so we need a larger population sample to determine the bene t of lymph node dissection on patients with small bowel cancer tumors, and to determine that this behavior will not be a burden on patients. According to the research results of Overman MJ et al., adequate nodal assessment is much less common in small bowel malignant tumor than large bowel malignant tumor; and it appears that small bowel malignant tumor, in particular duodenal malignant tumor, is understaged 12 .
Lymph node dissection, also called lymphadenectomy, was divided into LND (including limited LND and extended LND) and no LND, which could be essentially relevant with prognostic end of primary small intestinal tumor. Therefore, evaluating lymph node dissection in small bowel tumor surgery is of great signi cance to prevent negative outcomes. Several studies have demonstrated that LN metastasis is a negative prognostic factor in small bowel adenocarcinoma 6,13 . Limited by the data in the SEER database, we are unable to clarify the patient's disease choices and indications for surgery, but there are other studies that prove that lymph node dissection can make patients with small bowel tumors get greater bene ts in surgery. In our study, LND was performed in 86.4% of all patients treated with enterectomy.
According to reports by Wilhelm A et al, as the number of detected lymph nodes increased (>9), the number of positive lymph nodes detected also increased steadily, and the greater number of detected lymph nodes was also associated with a better prognosis, which is also in line with our research trends 14 .
According to result, younger age, non-white race, high grade, high T stage, unmarried, bigger tumor size, neuroendocrine adenocarcinoma were important factors to make LND decision.
Surgery is the most commonly used treatment for small bowel tumors 2,15 , and adjuvant chemotherapy has also been shown to play a role in improving the survival outcome of patients 16 .Up to now, the therapeutic effect of LND is still discussed controversially. From 2004 to the present, the number of lymph node dissections used in small bowel tumor resection has increased slightly, but the proportion of lymph node dissection and extended lymph node dissection have not changed signi cantly ( Figure S2-3). This may be due to increased physical examination leading to increased detection of small bowel tumors, but lymph node dissection and deep lymph node dissection have not increased. In other cancers, there has been a report that the proportion of LND is gradually increasing 17,18 , and this trend is not obvious in small intestine tumors, which may be caused by the rarity of small intestine tumors. Kaplan-Meier plots illustrated that extended LND with 4 or more regional lymph nodes removed might bene t OS for all T stage, but CSS only for pT1 obviously, and limited LND with 1 to 3 regional lymph nodes removed may bene t OS for all T stage except pT2 (Figure 2-3). In multivariable Cox regression analyses, we can see that extended LND may bene t for SBT patients for pT1, pT2 and pT4 stage both for OS and CSS. Compared to limited LND, extended LND can bring obvious bene ts, although at pT2 stage, also no obvious difference. Although the phenomenon in the pT2 stage is strange, further research is needed to consider. Doctors may need to be more careful when evaluating the stage of pT2 patients.
When comparing small intestinal neuroendocrine tumors with small intestinal non-neuroendocrine tumors, we can nd that they can also obtain signi cant bene ts from LND ( Figure S1). In the current clinical research, most researchers focus on primary small intestinal adenocarcinoma and small intestinal neuroendocrine tumors. Considering the rarity of small intestine tumors, we hope that LND can obtain similar bene ts in these subtypes. In COX analysis, extended LND has a signi cant survival rate in all stage diseases except pT2, while restricted LND has not signi cantly improved the survival outcome of patients, and neither of them has signi cantly bene ted patients in pT2 disease. However, this may also be due to selection bias. In any case, further prospective research is needed to verify. Up to now, there have been several studies supporting the comprehensive and thorough lymph node dissection of small bowel tumors in order to obtain better survival bene ts. According to Arnaud Pasquer et al. 19 , they suggested that systematic, extensive LN resection may be required to prevent unresectable locoregional recurrence in retropancreatic portion, as a result of skip metastases. Sophie Lardière-Deguelte et al. 20 evaluated the correlation between the length of resected small bowel and the number of removed LNs, and to propose a preoperative morphological classi cation of siNET-associated LNs. They believe that the best lymph node dissection is not simply a prolonged small bowel resection, but that the classi cation of mesenteric LNs should be standardized to help standardize the management of NET patients. According to Benjamin M Motz's report 21 , about 20% of patients with small bowel cancer resection from The National Cancer Database have not received lymph node dissection, although this can bring some benign effects.
Our research is still subject to some restrictions, which may affect our conclusion to a certain extent. First, we excluded patients with incomplete information from the study, and this selection method may cause selection bias. The region and economic status of the patients in the database, the level of hospitals receiving doctors and the experience of doctors are different. These factors may also lead to bias in the selection of LND. Secondly, our study is an observational study rather than an experimental study, and patients entering each cohort are not random, so the covariates we consider are not su cient to consider all risk factors of patients. Finally, due to the speci city of small intestine tumors, the area where the tumor is located is very different, so the range of LND is also di cult to determine, and this variable lacks standardization.

Conclusions
LND is performed more frequently in patients with locally advanced primary malignant small bowel tumors. In pT1/3/4 disease, the bene cial effect of LND with 4 or more regional lymph nodes removed on survival is obvious, but pT2 is gone. In addition, we found that a more adequate LND can bring bene ts that are signi cantly better than the restricted LND with only 1-3 lymph nodes removed, which can be observed in neuroendocrine tumors and non-neuroendocrine tumors. For patients with pT1, pT3, and pT4, LND can be considered, and a su cient LND is recommended. pT2 is still to be observed, which will be veri ed by further prospective studies.

Availability of data and materials
The data sets used and analyzed during this current study are available from the corresponding author on reasonable request. The authors have obtained permission from the Surveillance, Epidemiology and End Results database for patient information(not reveal personal privacy).

Ethics approval and consent to participate
For the institutional cohorts, data were extracted from the Surveillance, Epidemiology and End Results database. This article does not include any studies conducted by the authors with human participants. For this type of study,        Kaplan-Meier plots depicting overall survival and cancer-speci c survival according to LND extent status in speci c-stage pT1, pT2, pT3 and pT4 disease.
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