Clinical significance of positive resection margin for patients with rectal neuroendocrine tumors within 20mm following initial endoscopic resection: A multi-center study

doi:10.21203/rs.3.rs-4346045/v1

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Clinical significance of positive resection margin for patients with rectal neuroendocrine tumors within 20mm following initial endoscopic resection: A multi-center study

https://doi.org/10.21203/rs.3.rs-4346045/v1

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Background

The incidence of rectal neuroendocrine tumors (RNETs) has witnessed a significant surge, with a notable proportion being amenable to endoscopic removal. However, the clinical significance of positive resection margin for RNETs patients following endoscopic resection remain unknown, resulting in a lack of consensus regarding the appropriateness of implementing salvage treatment.

Methods

In this large, multicenter, retrospective cohort study, we analyzed the medical records of individuals who underwent endoscopic resection for RNETs and classified them into two groups: the positive resection margin and the negative resection margin group. The overall survival (OS) and disease-free survival (DFS) were compared among two group. The independent variables were identified using univariate and multivariate logistic regression analyses to predict positive resection margin. Then, the model was established to predict the patients with positive resection margin using multivariate logistic regression.

Results

181 RNETs patients (34.3%) represented positive margin after endoscopic resection. Following a median follow-up period of 72 months, tumor recurrence manifested in 12 out of 527 patients (2.2%) and the presence of positive resection margin was associated with worse DFS. Independent factors correlating with positive resection margin included endoscopic resection method choice, RNETs located in the low rectum, NLR > 4.44 and tumor size exceeding 14.89 mm. A prediction model was therefore established with high predictive accuracy and excellent clinical applicability determined by calibration curves and DCA curve. Among RNETs patients with positive margin following endoscopic resection, implementing salvage treatment was beneficial for improving DFS and salvage endoscopic resection offer equal efficiency compared with salvage radical resection .

Conclusions

Positive resection margin following endoscopic resection may indicate negative prognosis. Salvage treatment can improve the prognosis of RNETs patients with positive resection margin. Notably, salvage local resection exhibited similar efficacy compared with radical surgery in term of survival benefit.

RNETs

endoscopic resection

positive resection margin

salvage treatment

Neuroendocrine tumors (NETs) are the predominant endocrine neoplasms in the gastrointestinal tract¹, with the rectum emerging as the second most prevalent site for gastrointestinal NETs². The escalating incidence of colorectal NETs³ in recent decades can be attributed to the widespread adoption of screening colonoscopy⁴. Both the guidelines from the European Neuroendocrine Tumor Society (ENETS)⁵ and the North American Neuroendocrine Tumor Society (NANETS)⁶ advocate for local resection in cases where tumors are < 2 cm and confined to the submucosa. Given the relatively modest size of most rectal NETs (RNETs) and their infrequent association with metastasis at the point of initial diagnosis, endoscopic removal is often deemed feasible.

Positive resection margin could be observed in 19.8%-36.4% of RNETs patients following endoscopic resection⁷. In the assessment of rectal operations, a positive margin assumes critical importance indicative of worse prognosis and regarded as a sign of the need for salvage treatment⁸. Consequently, relevant guidelines advocate for salvage radical surgery following endoscopic resection in cases where RNETs exhibit a positive resection margin⁹. Recently, several retrospective studies have witnessed a low recurrence rate among RNETs patients with positive resection margin following endoscopic resection^10,11, which resulted in the question about the clinical significance of positive resection and a lack of consensus regarding the management strategy after the endoscopic resection of RNETs patients revealing a positive resection margin. However, the limited value of these studies, attributable to their single-center design, relatively short follow-up periods, and small study populations, restricts their capacity to effectively challenge the necessity of salvage treatment for RNETs with positive resection margins.

This study systematically assessed all pertinent clinical and pathological data associated with RNET cases in a large-scale multi-center cohort, with particular attention to the resection margin status. The primary objectives of this study were to elucidate the clinical significance of positive resection status for RNETs following endoscopic resection and to establish a clinical model for predicting the positive resection margin for RNETs patients following endoscopic resection. The secondary objective was to evaluate the clinical relevance of the salvage treatments for RNETs patients with positive resection margin and compare the efficacy of different salvage treatments.

Patients and clinical indices

Between December 2013 and June 2020, a total of 527 patients were diagnosed with RNETs after receiving endoscopic resection at five hospitals, namely the Sixth Affiliated Hospital of Sun Yat-sen University, the Fourth Affiliated Hospital of Dali University, the People's Hospital of Shenqiu County, the Third People’s Hospital of Shenzhen, and the Third Affiliated Hospital of Zunyi Medical University. The treatment details and prognostic outcomes of these patients were retrospectively obtained and analyzed in this study. Exclusion criteria encompassed cases exhibiting (1) invasion of the muscularis propria or (2) NET grading = 3, (3) metastasis to regional lymph nodes or distant organs at the time of diagnosis, (4) insufficient follow-up information (< 24 months), (5) presence of multiple primary tumors, (6) utilization of surgical excision or inappropriate methods such as forceps removal, and (7) a history of malignant tumors. Eventually, a total of 527 patients meeting the inclusion criteria were enrolled in the study. A schematic depiction of the patient selection process is presented in Fig. 1.

The clinicopathological information and follow-up data were all obtained from the hospital database. Approval for the execution of this study was obtained from the ethics committee of each participating hospital. The present study conducted in accordance with the ethical guidelines of the Declaration of Helsinki received approval from the institutional review board of all participating hospitals. This trial is duly registered with ClinicalTrials.gov under the identifier NCT06143605.

Endoscopic resection methods

All endoscopic procedures were conducted by experienced endoscopists specializing in rectal neoplasms. The assessment and documentation of resection methods for RNETs were performed for each case. These methods encompassed conventional endoscopic mucosal resection (EMR), cap-assisted endoscopic mucosal resection (EMR-C), precutting before endoscopic mucosal resection (EMR-P), and endoscopic submucosal dissection (ESD). The resection margin status, as well as procedure-related complications and their subsequent treatment, were also evaluated. Endoscopic complete resection was determined through a review of procedure reports and defined as a resection with a clear submucosal layer at the base. The classification of tumor shape was established as either sessile (Is) or mixed (Isp) types in accordance with the Paris-Japanese classification.

Pathology assessment

The H/E sections of all specimens were independently re-reviewed by two pathologists specializing in colorectal cancer to validate the findings. Microscopic assessment of all resected lesions included an examination of histopathologic type, size, margin status, tumor depth, NET grading, and the degree of lymphovascular invasion. Pathological reports served as the basis for determining tumor size and resection margin status. The classification of resection margin status as positive or negative was assigned based on criteria that deemed it "positive" if tumor cells extended into the lateral or vertical resection margins, the specimens were fragmented, or other situations resulted in difficulties in evaluating margins. The determination of the tumor grade for RNETs adhered to the 2010 World Health Organization (WHO) criteria, utilizing the mitotic index, the Ki-67 index, and histology as parameters, NETs grading G2 was characterized by a mitotic index of 2–20 mitoses/2 mm² and/or a Ki-67 index of 3–20%. Pathologists, through immunohistochemistry staining for four DNA mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2), identified patients' mismatch repair status as either mismatch-repair-deficient (dMMR) or mismatch-repair-proficient (pMMR) in cases where any of the mentioned proteins exhibited complete absence in nuclear staining of tumor cells.

Salvage treatment

Salvage treatment was administered to certain patients with NETs at the discretion of surgeons. The treatment modalities were categorized into radical surgical treatments and local excision (endoscopic interventions and transanal minimally invasive surgery (TAMIS)).

Follow-up information

The initiation of follow-up occurred on the surgery date and concluded on October 14, 2022. Follow-up assessments were conducted at three-month intervals during the initial year, semiannually from 1 to 5 years, and annually thereafter. Modalities employed for follow-up encompassed outpatient and inpatient re-examinations, examination of medical records, and telephonic follow-up. Standard examination parameters comprised clinical physical assessments, carcinoembryonic antigen (CEA) testing, and imaging examinations. Additionally, patients were advised to undergo pelvic MRI and colonoscopy annually. The principal outcomes under investigation in this study comprised overall survival (OS) and disease-free survival (DFS). DFS was operationally defined as the duration from surgery to the occurrence of local or distant failure or death, while OS was defined as the time from diagnosis to death from any cause.

Statistical analysis

IBM SPSS Statistics 26.0, R (version 4.0.0), and GraphPad Prism (version 8.0) was employed for all data analyses in this study. The chi-square test served as the primary method for determining classification criteria, with the recording of the number and proportion of cases. The analysis of continuous variables and the depiction of means utilized either the Mann-Whitney U-test or Student's t-test. The impacts of positive resection margin on the DFS and OS were assessed using the Kaplan–Meier method and compared with the log-rank test. Independent variables associated with positive resection margin were evaluated using the using multivariate logistic regression. Results were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). It was considered statistically significant when the 2-tailed P value was < 0.05.

The reporting of this study adheres to the STROCSS statement¹².

Establishment of the predictive model

According to a 7:3 ratio, the cohort was randomly separated into the training and validation sets. The predictive model was established based on the training group and using multivariate logistic regression. The optimal cut-off for continuous variables in predicting positive resection margin was determined through the area under the curve (AUC) in the receiver-operator characteristic (ROC). When the AUC > 0.75, the continuous variables would be presented as categorical variables (Fig. 2). Variables that attain statistical significance with a significance level of P < 0.05 in univariate testing are subsequently inserted in the multivariate model. This model was then used to predict RNETs patients with positive margin following endoscopic resection. Nomograms were used to present the model. The scores of each variable were superimposed and summed. In this way, the overall score was calculated individually and corresponded to the probability of positive resection margin. RNETs patients following endoscopic resection with a likelihood of more than 50% were considered candidates for positive resection margin.

Internal validation of the model and clinical application

The area evaluated the prediction performance of the nomogram under the curve of the receiver operating characteristic (AUC) of the training set and the validation set. The calibration plot and the Hosme-Lemeshow test were used to compare the predicted and observed outcomes (P > 0.05, the model adequately fits the data, without significant differences between the observational and forecast data). Decision curve analysis (DCA) is a fundamental statistical method used to evaluate the usefulness of a model in supporting clinical decision-making. The clinical effectiveness of the model was assessed by drawing the net benefit income within the clinically reasonable risk threshold. Based on the prediction model, when the predicted probability was more significant than 0.5, RNETs patients could benefit from the positive margin prediction.

A total of 686 patients with rectal tumors received a diagnosis of RNETs following initial endoscopic resection between 2013 and 2020. Among them, 527 patients were included in this study. After the endoscopic resection, positive resection margin was identified in 181 cases, representing 34.3% of the cohort (Fig. 1).

Clinicopathological characteristics

The median age of the 527 patients in this cohort was 59 years (range: 38–78 years), with 342 patients (64.9%) being male. A majority of the patients (81.4%) were asymptomatic, and all individuals underwent treatment exclusively through endoscopic modalities. Preceding treatment, 47 patients (8.92%) underwent endoscopic ultrasound (EUS). 358 patients (88.0%) underwent abdominal imaging modalities and no instances of regional lymph node involvement or distant metastases were detected at the initial diagnosis. Regarding tumor characteristics observed during endoscopic evaluation, central depression was identified in 25 patients (4.74%), erosion in 13 patients (2.47%), and a surface ulcer in 24 patients (4.55%). Endoscopic complete resection (R0 resection) was successfully accomplished in 346 patients (65.7%). The median pathological tumor size measured 14.62[13.52, 15.80] mm, within a range of 10.08–20.00 mm. Lymphovascular invasion was present in 30 patients (5.69%), while 24 patients exhibited perineural invasion. NETs grading G2, characterized by a mitotic index of 2–20 mitoses/2 mm² and/or a Ki-67 index of 3–20%, were identified in 89 patients (16.89%). A comprehensive summary of patient characteristics is provided in Table 1.

Table 1

Comparison of clinicalopathological features in RNETs patients following endoscopic resection, with positive or negative margin.
Variables	Total (n = 527)	Negative resection margin (n = 346)	Positive resection margin (n = 181)	P value
Age (years)
Median [IQR]	59.00[50.00,66.00]	59.00 [50.00, 66.00]	59.00 [50.00, 66.00]	0.853
Sex
Female	185 (35.10)	113 (32.66)	72 (39.78)	0.126
Male	342 (64.90)	233 (67.34)	109 (60.22)
BMI
Median [IQR]	22.59[20.41,24.73]	22.50[20.34, 24.66]	22.66[20.52, 25.00]	0.556
Symptom at diagnosis (%)
Abdominal pain	26 (4.93)	15 (4.34)	11 (6.08)	0.600
Hematochezia	11 (2.09)	7((2.02)	4 (2.21)
Bowel habit change	61 (11.57)	43(12.43)	18 (9.94)
No symptom	429 (81.40)	281 (81.21)	148 (81.77)
Rectal EUS (%)	47 (8.92)	32 (9.25)	15 (8.29)	0.857
Abdominal imaging (%)
Before endoscopic resection
Abdominal US	84 (15.94)	52 (15.03)	32 (17.68)	0.213
Abdominopelvic CT	60 (11.39)	38(10.98)	22 (12.15)
Both	57 (10.82)	36 (10.40)	21 (11.60)
After endoscopic resection
Abdominal US	427 (82.16)	267 (77.17)	160 (88.40)	0.157
Abdominopelvic CT	387 (72.90)	224 (64.74)	163 (90.06)
Endoscopic methods
EMR	213 (40.42)	127 (36.71)	86 (47.51)	< 0.001
EMR-C	199 (37.76)	109 (31.50)	90 (49.72)
ESD	113 (21.44)	109 (31.50)	4 (2.21)
EMR-P	2 (0.38)	1 (0.29)	1 (0.55)
Shape
Is	329 (62.43)	211 (60.98)	118 (65.19)	0.394
Isp	198 (37.57)	135 (39.02)	63 (34.81)
Surface change characteristics
Ulcer	24 (4.55)	18 (5.20)	6 (3.31)	0.746
Depression	25 (4.74)	16 (4.62)	9 (4.97)
Erosion	13 (2.47)	6 (1.73)	7 (2.35)
Length of tumor (mm)
Mean [IQR]	14.62[13.52, 15.80]	14.10 [13.26, 14.98]	15.77 [14.95, 16.98]	< 0.001
Submucosal invasion
Mucous	403 (76.47)	267 (77.17)	136 (75.14)	0.679
Submucosa	124 (23.53)	79 (22.83)	45 (24.86)
NET gradings
G1	431 (81.78)	284 (82.08)	147 (81.22)	0.440
G2	89 (16.89)	59 (17.05)	30 (16.57)
Lymphovascular invasion
Negative	497 (94.31)	325 (93.93)	172 (95.03)	0.750
Positive	30 (5.69)	21 (6.07)	9 (4.97)
Perineural invasion
Negative	503 (95.45)	330 (95.38)	173 (95.58)	1.000
Positive	24 (4.55)	16 (4.62)	8 (4.42)
Microsatellite status
pMMR	344 (88.43)	239 (91.57)	105 (82.03)	0.009
dMMR	45 (11.57)	22 (8.43)	23 (17.97)
9

Oncological outcomes

Following a mean follow-up period of 72 months (range: 38–126 months), tumor recurrence manifested in 12 out of 527 patients (2.2%). Among these cases, eight patients exhibited distant metastasis, four experienced local recurrence, and one patient encountered both local recurrence and distant metastasis. Ultimately, night patients (1.7%) died during the follow-up duration. RNETs patients with positive resection margin following endoscopic resection got worse survival and DFS rate witness the statistical difference.

Nomogram to identify positive resection margin and evaluation of the model

Independent prognostic factors from Table 2 were included in the prediction nomogram. The model showed RNETs patients following endoscopic resection with tumor size > 14.89 mm, tumor located in the low rectum, and NLR > 4.44 would more likely to be associated with positive margin, and ESD is least risky of positive resection margin (Fig. 4A). This predictive model can effectively select patients in the training (AUC = 0.967) and verification (AUC = 0.872) sets who may diagnosed positive resection margin (Fig. 4B and C).The training set and validation set calibration curves confirmed the good predictive accuracy between the actual observation probability and predicted probability. DCA showed that for RNEs patients, “using the model to predict positive resection margin” provided benefit in supporting clinical decision-making (Fig. 4D).

Table 2

Univariable and multivariable analysis of factors associated with positive resection margin using logistic regression model for 527 RNETs patients.
Factors	Univariate analysis	Multivariate analysis
Factors	P value	HR (95% CI)	P value
Tumor size	< 0.001	15.64 (4.50-54.39)	< 0.001
Tumor location	< 0.001	7.61 (2.37–24.44)	< 0.001
Endoscopic resection method	< 0.001	0.41 (0.20–0.85)	0.016
CA19-9	0.008	2.12 (0.64–7.06)	0.221
CEA	0.067
dMMR status	0.009	0.50 (0.07–3.52)	0.478
lymphocyte count (median [IQR])	< 0.001
Neutrophil count (median [IQR])	< 0.001	107.76(0.00-Inf)	0.989
Leukocyte count (median [IQR])	< 0.001	0.00 (0.00-Inf)	0.992
NLR (median [IQR])	< 0.001	4.60 (1.30-16.33, p = .018)	0.018
platelets count (median [IQR])	0.045
CRP (median [IQR])	0.111
monocyte (median [IQR])	0.342
TP (median [IQR])	0.137
ALB (median [IQR])	0.094
PLR (median [IQR])	< 0.001
PNI (median [IQR])	0.057

Association between positive resection margin and salvage treatment

Statistically significant improvement was observed in the DFS rate across RNETs patients with positive margin undergoing salvage treatment following initial endoscopic resection compared with follow up group while OS rate did not witness the significance (Fig. 5). Notably, salvage local resection including endoscopic resection and transanal resection exhibited similar efficacy compared with radical surgery (Fig. 6).

In this study, we conducted a comprehensive evaluation of the long-term clinical outcomes in a cohort comprising 527 patients with RNETs who underwent endoscopic resection across multiple centers in China. Notably, salvage treatment conferred a benefit specifically to cases with positive resection margin.

The majority of RNETs were small (< 10mm) and localized at the initial diagnosis, known for their relatively indolent nature, with a 5-year survival rate of 90%^13,14. Endoscopic excision is deemed a viable approach for RNETs¹⁵. However, challenges related to the submucosal location and limited operative space contribute to a relatively high rate of positive resection margins in endoscopically resected RNETs. A low recurrence rate was observed in RNETs patients with positive resection margins after endoscopic resection. However, existing literature on the long-term clinical outcomes and risk factors for recurrence or metastasis of endoscopically resected RNETs with positive resection margin does not offer a comprehensive understanding, as previous studies were limited by small sample sizes or the inclusion of surgically resected cases. Addressing resection margins, current expertise advocate for perspective that endoscopists should be concerned with the possibility of metastasis during long-term follow-up of RNETs patients with positive resection margin and consider salvage treatment¹⁶. Our research extends this understanding, demonstrating that a positive resection margin correlates with a worsened prognosis for RNETs during a more extended follow-up period.

Salvage treatment significantly improves survival for RNETs patients with positive resection margin following endoscopic resection in our research. Nevertheless, the decision to proceed with salvage surgery in such instances is often challenging in real-world clinical practice, given the considerable invasiveness associated with rectal surgery. Local excision exhibits comparable efficacy to radical surgery in previous research addressing initial resection¹⁷. Notably, this research also advocated for a less invasive option following a positive resection margin since there was no survival benefit for salvage radical surgery compared with salvage local resection. These findings suggest that less invasive local resection may be imperative for RNETs patients with a positive resection margin.

This study predicted the likelihood of positive margin in RNETs patients following endoscopic resection with validated predictive efficacy and thus allows for individualize treatment. Our model demonstrated that endoscopic resection method choice, RNETs located in the low rectum, NLR > 4.44 and tumor size exceeding 14.89 mm are the most significant factors associated with positive resection margin. To date, prediction of the behavior of rectal NETs has been mainly based on initial pathologic tumor sizes. Large tumors size was associated with increase rate of positive margins¹⁰, and the worsen prognosis of positive margins may be related to this. Different local excision modalities result in different rate of positive margins, and current guidelines are inconclusive as to which type of endoscopic resection to use. Our study demonstrated that for RNET patients, ESD had the lowest incidence of positive margins, and this needs to be verified in future prospective studies.

This is the first population-based study to identify the tumor location and inflammatory indexes “NLR” as risk factors for positive margin among RNETs patients following endoscopic resection. Positive margins are more likely to occur when the tumor is located < 5cm to the anus, which we believe is related to a smaller operating space by endoscopic resection and transanal method served as a better option under such circumstance. Many serum markers of systemic inflammation including NLR have proven to be useful in measuring surgical trauma. The predictive effect on positive margins among RNETs patients following endoscopic resection was found for the first time. Additionally, NLR has proven to be useful in guiding patient prognosis^18,19, and the association of NLR with positive margins worsening the prognosis for RNETs patients needs further investigation.

In conclusion, our study fills a gap in the current knowledge of RNETs patients following endoscopic resection as related to positive resection margin. This study has several limitations. The primary limitation is its retrospective design; however, standardized guidelines for staging and surveillance mitigate bias, enhancing the credibility of our conclusions. Additionally, rectal EUS, recommended for evaluating the depth of invasion during initial staging, was performed in only 8.9% of patients in our study. Muscularis propria invasion was rarely observed and consequently excluded from our study. Thirdly, our focus solely on RNET patients undergoing endoscopic resection precludes an analysis of initial radical resection. We intend to address this gap by reporting the results of a similar study involving radical resection in the near future.

RNETs patients with positive resection margin following endoscopic resection may indicate negative prognosis. Tumor located in the low rectum, NLR > 4.44 and tumor size exceeding 14.89 mm are the most significant factors associated with positive resection margin. Salvage treatment can improve the prognosis of RNETs patients with positive resection margin. Notably, salvage local resection exhibited similar efficacy compared with radical surgery in term of survival benefit.

CONFLICT OF INTEREST STATEMENT

The authors declare there is no conflict of interest.

Author Contribution

Thank all the patients who participated in this study and all the authors for their contributions to the article ; Conceptualization: L.H. and F.J.YData curation: D.X.L. and Y.B.H.Z Formal analysis: H.X. and W.X.Funding acquisition: P.Z.H and L.H.Investigation: L.R. and W.L.Z.Methodology: F.J.Y. , Y.X.S. and P.Z.H.Project administration: Z.Z.L.and W.L.ZResources: Z.L. and Z.Z.L.Software: X.B.Z and Z.X.L.Supervision: L.H. and L.K.Validation: H.S.L. and Z.Z.L.Visualization: H.Q.Z and Z.Z.LWriting – original draft: F.J.Y. and Z.Z.L.Writing – review & editing: M.P.D, Y.Q. and L.H.

ACKNOWLEDGEMENTS

This study was supported by the National Key Clinical Discipline, Science and technology key research and development plan project of Guangzhou (China) (202103000072), Natural Science Foundation of Guangdong Province (China) (2018A030313621), Science and Technology Projects in Guangzhou (202206010062), Sun Yat-sen University Clinical Research 5010 Program (2016005), and Shenzhen “San Ming Projects” Research (Grant No.lc202002).

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Clinical significance of positive resection margin for patients with rectal neuroendocrine tumors within 20mm following initial endoscopic resection: A multi-center study

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Abstract

Background

Methods

Results

Conclusions

Figures

INTRODUCTION

METHODS

Patients and clinical indices

Endoscopic resection methods

Pathology assessment

Salvage treatment

Follow-up information

Statistical analysis

Establishment of the predictive model

Internal validation of the model and clinical application

RESULTS

Clinicopathological characteristics

Oncological outcomes

Nomogram to identify positive resection margin and evaluation of the model

Association between positive resection margin and salvage treatment

DISCUSSION

CONCLUSIONS

Declarations

CONFLICT OF INTEREST STATEMENT

Author Contribution

ACKNOWLEDGEMENTS

References

Additional Declarations

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