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Abstract

Background and aims:

Patients with small intestinal neuroendocrine tumors (siNETs) frequently present emergently due to bowel ischemia or bowel obstruction. The influence of emergency surgery on the prognosis of siNET remains controversial. The aim of this study was to investigate the association between type of presentation (emergency/elective) and oncological outcome.

Methods:

Clinicopathological data of patients who underwent bowel resection and were treated due to siNET at the Charité — Universitätsmedizin Berlin, Germany were analyzed retrospectively.

Results:

A total of 165 patients underwent bowel resection for siNET. Of these, 22.4% (n = 37) were emergency and 77.6% (n = 128) were elective procedures. A preoperative known diagnosis was less common in patients with emergency surgery (48.6% vs 85.2%; p < 0.001) and complete resections of all tumor manifestations were performed less often (32.4% vs 50.8%; p = 0.049), while more completion operations had to be performed (24.3% vs 11.1%; p = 0.049). Overall survival (OS) and progression-free survival (PFS) of emergently operated patients were reduced (5-year OS: 85.2% vs 89.5% (p = 0.023); 5-year PFS: 26.7% versus 52.5% (p = 0.018)). In addition, emergency surgery was negatively associated with OS after multivariable regression analysis.

Conclusion:

Emergency surgery in siNET patients is associated with adverse oncological outcomes including shorter OS and PFS. Prevention of emergency conditions should be emphasized in advanced disease.

Keywords

Small intestinal neuroendocrine tumors emergency surgery oncologic outcome

Twitter summary

A relevant part of patients suffering from small intestinal neuroendocrine tumors (siNETs) present with conditions requiring emergency surgery such as small bowel obstruction or bowel ischemia. Analyses of the impact of emergency surgery on oncological outcome in these patients revealed conflicting results. This study includes a retrospective outcome analysis of siNET patients treated at Charité — Universitätsmedizin Berlin comparing patients operated in elective and emergency settings. We demonstrate impaired overall and progression-free survival in siNET patients undergoing emergency surgery. The findings suggest that in siNET patients adequate diagnostic work-up and early elective surgery should be promoted to prevent NET-associated complications and the need for emergency surgery. Moreover, more intense follow-up and more aggressive medical therapy management in siNET patients following emergency surgery should be discussed.

Context and relevance

A relevant part of patients suffering from siNETs present with conditions requiring emergency surgery such as small bowel obstruction or bowel ischemia. Until now, analyses of the impact of emergency surgery on oncological outcome in these patients revealed conflicting results. This study includes outcome analyses of patients undergoing small bowel resection for siNET comparing patients operated in elective and emergency settings. We demonstrated impaired overall and progression-free survival in siNET patients undergoing emergency surgery. Possible reasons were fewer curative operations, higher incidence of carcinoid heart disease and increased number of patients with distant metastases. Emergency surgery was found a negative prognostic factor for overall survival. This finding promotes adequate diagnostic work-up and early elective surgery to prevent NET-associated complications and the need for emergency surgery. Finally, closer postoperative follow-up and therapy management in siNET patients following emergency surgery should be discussed.

Introduction

Small intestinal neuroendocrine tumors (SiNETs) are the most common subtype within the group of gastroenteropancreatic NETs.¹ Symptoms usually appear in advanced stages and may include unspecific symptoms, for example, abdominal pain or gastrointestinal bleeding as well as hormone-related symptoms such as diarrhea and flushing. Owing to this relatively indolent behavior, most siNETs are diagnosed when already metastasized to lymph nodes or distant organs.² The only curative treatment is surgical resection of all tumor manifestations. However, even patients with metastatic and/or unresectable disease face a relatively good prognosis, especially in well and moderately differentiated tumors.³

In many cases, mesenteric fibrotic mass formation occurs around lymph node metastases due to a so-called desmoplastic reaction, which can be detected radiologically by its characteristic stellate or spoke-wheel appearance.^4,5 Mesenteric fibrosis can lead to various complications, including deterioration of bowel function, which can result in acute bowel obstruction or intestinal ischemia.⁶ Patients presenting with these conditions often require emergency surgery, leaving little time for additional diagnostics. Recommendations for appropriate management in such are vague, and evidence on oncological outcome is scarce. Some studies indicate comparable outcomes for emergency and elective surgery in siNET patients,⁷ while others report earlier disease recurrence and shorter survival for patients undergoing emergency surgery.^3,8 Elective surgery, on the contrary, is typically performed in patients with histologically proven siNET, often diagnosed by colonoscopy or the detection of liver metastases. Nevertheless, the timing of surgery for patients with distant metastases remains a critical and individualized decision, essential for effectively preventing acute bowel obstruction or ischemia.^9,10

In gastrointestinal surgery, studies show poorer postoperative outcomes in emergency patients, with higher complications rates and short-term mortality compared to elective patients.^11,12 In malignant diseases, such as colorectal cancer, initial emergency surgery is associated with impaired long-time oncological outcome.^13–15

Since emergencies requiring immediate surgery are unpredictable, understanding their impact on oncological outcomes is crucial. This study aimed to evaluate the association between emergency or elective surgery and oncological outcome in siNET patients. We hypothesized that emergency surgery is a risk factor for impaired outcome.

Methods

Patient demographic and clinical data

Patients treated for siNET at the European Neuroendocrine Tumor Society (ENETS) Center of Excellence at the Charité — Universitätsmedizin Berlin, Germany between January 2010 and December 2020 were identified from the Charité Comprehensive Cancer Center (CCCC) database. The study included patients who underwent resection of the primary tumor; with diagnosis established either prior, during, or after surgery. Exclusion criteria were non-resection of the primary tumor, age under 18 years, G3 NETs, neuroendocrine carcinomas, and missing data on urgency indication. Data retrieved from medical charts included age, sex, American Society of Anesthesiologists (ASA) status, tumor stage (UICC 8th edition),¹⁶ tumor node metastasis (TNM) classification and tumor grading according to the World Health Organization (WHO) grading system. Carcinoid syndrome was defined as the combination of flushing and diarrhea and/or wheezing; carcinoid heart disease (CHD) was defined as the presence of tricuspid valve insufficiency diagnosed by echocardiography. Lymph node spread patterns were classified into locoregional (stage I–II according to Ohrvall et al.),¹⁷ central (stage III), and extended central including retroperitoneally extending lymph nodes and peripancreatic lymph nodes (stage IV). Hepatic tumor burden was identified via cross-sectional imaging. Time to surgery was calculated as time from diagnosis to surgery.

Surgery and histopathological data

Independent of preoperatively known siNET, indication for bowel resection was divided into elective surgery, including all electively planned abdominal surgeries, and emergency surgery, including all high urgent and emergency operations due to acute conditions requiring urgent surgery. The performance of systematic lymphadenectomy (LAD) was assessed. Details about resection margins and residual tumor classification (R status) were collected from the histopathological report. R status was defined as no (R0), microscopic (R1), and macroscopic (R2) evidence of residual tumor tissue. Bowel resections were grouped into partial ileal resection, ileocecal resection, right hemicolectomy, extended right hemicolectomy, right hemicolectomy and partial ileal resection, and other. Procedures including right hemicolectomy with/without small bowel resections were defined as extended resections. The resection was considered complete if all macroscopic tumor mass was removed and as incomplete if only tumor mass reduction could be achieved. This included cases where the primary and lymph node metastases were fully removed, but distant metastases remained. Secondary resections following incomplete primary resections were termed completion surgery. Postoperative complications were classified according to Clavien–Dindo; major complications were defined as ⩾3a.¹⁸

Follow-up parameters

Patients were followed up according to the ENETS consensus guidelines¹⁹ with data included through 31 December 2022. Disease progression was determined by an interdisciplinary tumor board based on clinical assessment, laboratory markers (Chromogranin A), and cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging [MRI] and somatostatin receptor imaging) according to the response evaluation criteria in solid tumors (RECIST, version 1.1).²⁰ NET-related deaths including those due to siNET metastasis, tumor compression, CHD, or other conditions attributable to advanced siNET disease, were recorded based on medical records. Usage of adjuvant therapies was assessed.

Statistical analysis

Continuous variables are presented as medians (range) and categorical variables as frequencies and percentage. Group comparisons for continuous variables were performed using either the Mann–Whitney U-test or Kruskal–Wallis test. For categorical variables, the chi-square test or Fisher’s exact test were used. Survival analyses were performed according to the Kaplan–Meier method; survival rates were compared using log-rank tests. Overall survival (OS) was defined as time between bowel resection and death, progression-free survival (PFS) as time between bowel resection and first postoperative progress. Patients who did not reach the endpoints or were lost to follow-up were censored at the last follow-up visit. Univariable Cox regression analysis identified potential factors influencing OS and PFS with results displayed as hazard ratio (HR) with 95% confidence interval (95% CI). Multivariable Cox regression adjusted for confounders, including covariates with p < 0.1 in the univariable analysis. For OS, up to three variables were included, following the rule of 10 events per variable.^21,22 Known confounders for emergency surgery and OS included age,³ ASA score,^15,23 and preoperative diagnosis,³ of which age and ASA score were included. For PFS, up to nine variables could be included. Advanced tumor size (T3/T4),^7,8 lymph node metastasis (N1 status),^8,24,25 and distant metastasis.^{25,26 were identified as additional potential confounders.}

Statistical analyses were performed using SPSS Statistics software, version 27 (IBM Armonk, NY, USA). Missing data were indicated and were excluded analysis by analysis. The significance level was set to 0.05. The study was approved by the local Institutional Ethics Committee of Charité — Universitätsmedizin Berlin (EA2/064/09) and was conducted in accordance with the Declaration of Helsinki. All patients provided informed consent for registry participation, data collection, and analysis.

Results

Patient characteristics

Five hundred and ten patients with siNET were identified from the CCCC database, and 165 patients met the inclusion criteria (Fig. 1). Of these, n = 128 were operated in an elective setting, while n = 37 were emergency surgeries.

Fig. 1.

Patient inclusion and exclusion. siNET; small intestinal neuroendocrine tumor; CoE, center of excellence; NEC, neuroendocrine carcinoma.

Comparison of elective and emergency patients

Patient characteristics and a comparison between elective and emergency surgery cohorts are shown in Table 1. In the emergency group, the diagnosis was more often known preoperatively, and extended and complete resections were performed less frequently. Completion surgeries were more common, and adjuvant therapy including SSA therapy was used more frequently. Emergency patients had higher rates of postoperative disease recurrence or progression. They also tended to be older, have more T3/T4 tumors, higher 30-day mortality, more CHD, and more distant metastases, although these differences were not statistically significant. No differences were found regarding gender, ASA status, carcinoid syndrome, lymph node metastasis location, hepatic tumor burden, UICC stage, N stage, residual tumor classification, grading, Ki67, minor and major postoperative complications, 30-day morbidity, and multifocal tumor occurrence (Table 1).

Table 1.

Characteristics and comparison of siNET patients undergoing bowel resection in elective and emergency settings.

		Total n = 165	Elective n = 128	Emergency n = 37	p value
Gender	Male:female	72:93	58:70	14:23	0.419
Age (years)^a		61 (26–84)	60 (26–80)	65 (40–84)	0.076
ASA	1	6 (3.6%)	4 (3.1%)	2 (5.4%)	0.547
	2	105 (63.6%)	84 (65.6%)	21 (56.8%)
	3	54 (32.7%)	40 (31.3%)	14 (37.8%)
CHD		14 (8.5%)	8 (6.3%)	6 (16.2%)	0.071
Carcinoid syndrome		55 (33.3%)	41 (32.0%)	14 (37.8%)	0.521
Lymph node spread pattern	None	20 (12.1%)	18 (14.1%)	2 (5.4%)	0.398
	Locoregional	88 (53.3%)	69 (53.9%)	19 (51.4%)
	Central	45 (27.3%)	31 (24.2%)	14 (37.8%)
	Extended central	10 (6.1%)	8 (6.3%)	2 (5.4%)
	Unknown	2 (1.2%)	2 (1.6%)	0 (0.0%)
Distant metastasis		100 (60.6%)	73 (57.0%)	27 (73.0%)	0.080
Hepatic tumor burden (n = 80)	<25%	40 (50.0%)	31 (31.7%)	9 (45.0%)	0.424
	25%–50%	18 (22.5%)	12 (20.0%)	6 (30.0%)
	>50%	7 (8.75%)	6 (10.0%)	1 (5.0%)
	Unknown	15 (18.75%)	11 (18.3%)	4 (20.0%)
UICC	I	10 (6.1%)	9 (7.0%)	1 (2.7%)	0.426
	II	10 (6.1%)	9 (7.0%)	1 (2.7%)
	III	45 (27.3%)	37 (28.9%)	8 (21.6%)
	IV	100 (60.6%)	73 (57.0%)	27 (73.0%)
Preoperative diagnosis		127 (77.0%)	109 (85.2%)	18 (48.6%)	<0.001
Time to surgery (months)^a		0 (0–81)	1 (0–81)	0 (0–31)	0.143
Type of surgery	Partial ileal resection	58 (35.2%)	38 (29.7%)	20 (54.1%)	0.031
	Ileocecal resection	22 (13.3%)	17 (13.3%)	5 (13.5%)
	Right hemicolectomy	74 (44.8%)	65 (50.8%)	9 (24.3%)
	Extended right hemicolectomy	4 (2.4%)	3 (2.3%)	1 (2.7%)
	Right hemicolectomy and partial ileal resection	5 (3.0%)	4 (3.1%)	1 (2.7%)
	Other	2 (1.2%)	1 (0.8%)	1 (2.7%)
Extended resection		83 (50.3%)	72 (56.2%)	11 (29.7%)	0.004
Systematic LAD		117 (73.1%)	92 (74.8%)^b	25 (67.6%)	0.384
Complete resection		76 (46.6%)	64 (50.8%)	12 (32.4%)	0.049
Histopathological parameters
T stage	T1	16 (9.7%)	14 (10.9%)	2 (5.6%)	0.329
	T2	30 (18.2%)	26 (20.3%)	4 (11.1%)
	T3	68 (41.2%)	50 (39.1%)	18 (50.0%)
	T4	48 (29.1%)	37 (28.9%)	11 (30.6%)
	Tx	3 (1.8%)	1 (0.8%)	1 (2.8%)
T3/T4		116 (71.6%)	87 (68.5%)	29 (82.9%)	0.095
N stage	N0	27 (16.4%)	24 (18.8%)	3 (8.1%)	0.123
N stage	N1	138 (83.6%)	104 (81.3%)	34 (91.9%)	0.123
Lymph nodes resected^a		14 (0–91)	15 (0–91)	10 (0–44)	0.031
Lymph nodes positive^a		2 (0–27)	3 (0–27)	2 (0–16)	0.728
Residual tumor	R0	122 (74.0%)	97 (75.8%)	25 (67.6%)	0.141
	R1	33 (20.0%)	25 (19.5%)	8 (21.6%)
	R2	8 (4.8%)	4 (3.1%)	4 (10.8%)
	Rx	2 (1.2%)	2 (1.6%)	0 (0.0%)
M stage	M0	65 (39.4%)	55 (43.0%)	10 (27.0%)	0.080
M stage	M1	100 (60.6%)	73 (57.0%)	27 (73.0%)	0.080
Grading	G1	96 (58.2%)	77 (60.2%)	19 (51.4%)	0.339
Grading	G2	69 (41.8%)	51 (39.8%)	18 (48.6%)	0.339
Ki67 (%)^a		2 (1–20)	2 (1–20)	3 (1–20)	0.469
Multifocal		29 (17.6%)	24 (18.8%)	5 (13.5%)	0.461
Postoperative complications	Minor	32 (22.1%)	24 (21.4%)^c	8 (24.2%)^d	0.732
Postoperative complications	Major	15 (10.3%)	11 (9.8%)^c	4 (12.1%)^d	0.747
30-day morbidity		47 (32.4%)	35 (31.2%)^c	12 (36.3%)^d	0.825
30-day mortality		1 (0.6%)	0 (0.0%)	1 (2.7%)	0.224
	Follow-up
Progression		91 (55.1%)	63 (49.2%)	28 (75.7%)	0.004
Localization of progression (n = 91)	Locoregional	7 (7.7%)	5 (7.9%)	2 (7.1%)	1.000
	Distant	79 (86.8%)	54 (85.7%)	25 (89.3%)
	Both	5 (5.5%)	4 (6.3%)	1 (3.6%)
NET-related death		32 (19.4%)	21 (16.4%)	11 (29.7%)	0.071
Completion surgery		23 (14.4%)	14 (11.1%)	9 (24.3%)	0.049
Number of NET-related surgeries	1	117 (70.9%)	96 (75.0%)	21 (56.8%)	0.066
	2	37 (22.4%)	24 (18.8%)	13 (35.1%)
	⩾3	11 (6.7%)	8 (6.2%)	3 (8.1%)
Adjuvant therapy		96 (58.2%)	69 (53.9%)	27 (73.0%)	0.038
Additional therapies	SSA	94 (57.0%)	67 (52.3%)	27 (73.0%)	0.026
	PRRT	33 (20.1%	26 (20.5%	7 (18.9%)	0.974
	Everolimus	12 (7.3%)	9 (7.0%)	3 (8.1%)	0.645
	TAE/TACE	8 (4.8%)	5 (3.9%)	3 (8.1%)	0.374
	IFN	8 (4.8%)	5 (3.9%)	3 (8.1%)	0.374
	SIRT	6 (3.6%)	3 (2.3%)	3 (8.1%)	0.144
	Brachytherapy	6 (3.6%)	6 (4.7%)	0 (0.0%)	0.327
	Chemotherapy	5 (3.0%)	4 (3.1%)	1 (2.7%)	0.809

Values in parentheses are percentages unless indicated otherwise; values are ^amedian (range); ^bMissing data in n = 5 patients; ^cMissing data in n = 16 patient; ^dMissing data in n = 4 patient.

siNET: small intestinal neuroendocrine tumor; ASA: American Society of Anesthesiologists; CHD: carcinoid heart disease; UICC: Union for International Cancer Control; LAD: lymphadenectomy; SSA: somatostatin analogue; PRRT: peptide receptor radionuclide therapy; TAE: transarterial embolization; TACE: transarterial chemoembolization; IFN: interferone; SIRT: selective internal radiation therapy.

In the cohort of patients who underwent emergency surgery for siNET, the diagnosis was already established in n = 18 (48.6%) cases. The characteristics of these patients are detailed in Supplementary Table 1. Among those patients with a known diagnosis of siNET, n = 11 (61.1%) had planned surgery prior to emergency presentation, n = 4 (22.2%) had surgery recommended, and n = 3 (16.7%) were ineligible for surgery due to comorbidities including CHD. Seven patients were already receiving SSA therapy; and one patient had received peptide receptor radionuclide therapy (PRRT). Only time to surgery, which was shorter in patients without preoperative diagnosis, differed significantly.

Survival analysis

Within the median follow-up time of 66 months (interquartile range: 40–87 months), there were 32 (19.4%) deaths, with 21 in the elective cohort and 11 in the emergency group. Disease recurrence or progression was reported in 91 patients (55.1%), with 63 in the elective and n = 28 in the emergency group. As shown in Fig. 2A, OS in the elective surgery group was longer with a median estimated survival of 14.1 years (95% CI: 9.4–18.8) versus 8.3 years (95% CI: 3.3–13.4) and 5-year survival rates of 89.5% (95% CI: 82%–94%) compared to 85.2% (95% CI: 68%–94%). PFS was also longer in the elective surgery group with median estimated survivals of 6.1 years (95% CI: 3.9–8.2) versus 2.8 years (95% CI: 2.4–3.3) and a 5-year PFS rate of 52.5% (95% CI: 43%–61%) versus 26.7% (95% CI: 13%–42%) (Fig. 2B).

Fig. 2.

Comparison of a. overall survival and b. progression-free survival in siNET patients undergoing bowel resection in elective and emergency settings. Elective patients showed longer overall survival (5-year overall survival: 89.5% vs 85.2%, p = 0.023) as well as progression-free survival (5-year progression-free survival: 52.5% vs 26.7%, p = 0.018) than emergency patients. Survival rates were compared using log-rank tests. Censored data are marked with ticks.

Cox proportional hazard model—Overall and progression-free survival

To identify the association of emergency surgery with OS and PFS, univariable and multivariable Cox regression analysis were performed. In the univariable model ASA3 status, carcinoid syndrome, emergency surgery, positive resection margins, distant metastases, tumor multifocality, and debulking surgery were identified as negative prognostic factors for OS (Table 2). After adjusting for confounding of age and ASA 3 in the multivariable regression analysis, emergency surgery was confirmed to increase the risk for impaired OS with an HR of 2.281 (95% CI: 1.077–4.834). Regarding PFS, univariable analysis revealed CHD, emergency surgery, T3/T4 status, N1 status, tumor grading, distant metastasis, and incomplete surgery as negative prognostic factors (Table 3). When adjusting for T3/T4 status, N1 status and distant metastasis, no effect of emergency surgery on PFS was observed.

Table 2.

Univariable and multivariable Cox regression analysis for variables affecting OS in siNET patients.

	Univariable		Multivariable
	HR (95% CI)	p value	HR (95% CI)	p value
Female gender	1.247 (0.615–2.528)	0.540
Age	1.033 (0.997–1.070)	0.070	1.023 (0.987–1.061)	0.215
ASA 3	2.119 (1.047–4.287)	0.037	1.915 (0.921–3.981)	0.082
CHD	2.148 (0.860–5.367)	0.102
Carcinoid syndrome	2.753 (1.349–5.620	0.005
Preoperative diagnosis	0.846 (0.388–1.842)	0.673
Emergency surgery	2.312 (1.098–4.868)	0.027	2.281 (1.077–4.834)	0.031
T3/T4	2.192 (0.834–5.764)	0.112
Extended resection	0.572 (0.280–1.171)	0.127
N1 status	3.227 (0.768–13.555)	0.110
Positive resection margin	2.184 (1.037–4.597)	0.040
Grading	1.810 (0.901–3.635)	0.095
Distant metastasis	2.779 (1.140–6.779)	0.025
Multifocal	5.325 (1.158–24.491)	0.032
Incomplete surgery	4.127 (1.692–10.069)	0.002
Completion surgery	0.403 (0.121–1.350)	0.141
Systematic LAD performed	0.615 (0.292–1.297)	0.201

HR: hazard ratio; 95% CI, 95% confidence interval; ASA: American Society of Anesthesiologists; CHD: carcinoid heart disease; LAD: lymphadenectomy.

Table 3.

Univariable and multivariable Cox regression analysis for variables affecting PFS in siNET patients.

	Univariable		Multivariable
	HR (95% CI)	p value	HR (95% CI)	p value
Female gender	1.433 (0.938–2.190)	0.096
Age	1.002 (0.985–1.020)	0.784
ASA 3	1.362 (0.892–2.080)	0.152
CHD	2.691 (1.481–4.888)	0.001
Carcinoid syndrome	2.396 (1.583–3.624)	<0.001
Preoperative diagnosis	0.751 (0.476–1.185)	0.228
Emergency surgery	1.703 (1.089–2.665)	0.020	1.252 (0.790–1.984)	0.338
T3/T4	4.476 (2.313–8.662)	<0.001	1.776 (0.823–3.833)	0.143
Extended resection	0.964 (0.638–1.455)	0.860
N1 status	3.382 (1.561–7.326)	0.002	1.508 (0.656–3.462)	0.333
Positive resection margin	1.566 (0.987–2.485)	0.057
Grading	1.695 (1.122–2.559)	0.012
Distant metastasis	5.553 (3.133–9.843)	<0.001	4.037 (2.078–7.843)	<0.001
Multifocal	1.035 (0.602–1.780)	0.900
Incomplete surgery	3.504 (2.204–5.569)	<0.001
Completion surgery	1.001 (0.561–1.787)	0.996
Systematic LAD performed	0.943 (0.592–1.503)	0.804

HR: hazard ratio; 95% CI, 95% confidence interval; ASA: American Society of Anesthesiologists; CHD: carcinoid heart disease; LAD: lymphadenectomy.

Discussion

There is conflicting evidence regarding the oncological outcomes of patients undergoing emergency surgery for siNET. In this study, both OS and PFS of siNET patients were impaired in siNET patients who underwent emergency surgery. Possible reasons included older age, fewer curative operations, higher incidence of CHD, and more patients with distant metastases. Multivariable analysis further identified emergency surgery as risk factor for impaired OS.

Consistent with the literature, all siNET patients in the study cohort had a relatively good prognosis with 5-year OS rates of 89.5% in elective and 85.2% in emergency surgery patients.^27,28 When comparing the prognosis of elective and emergency siNET patients, the literature shows mixed results. Manguso et al. found no difference in oncological outcomes between siNET patients operated under elective and emergency conditions.⁷ Eriksson et al. even identified emergency surgery as favorable prognostic factor for OS. However, in their study, around 75% of the elective cohort (n = 99) had stage-IV disease, whereas approximately 75% of the emergency group (n = 194) were in stage I–IIIb²⁹ suggesting that disease stage, a known prognostic factor, likely confounded the outcomes, favoring emergency patients. In contrast, Folkestad et al.³ demonstrated shorter median OS in emergency patients and identified elective surgery as independent positive prognostic factor for survival, aligning with the results of this study.

The unfavorable oncological outcomes observed in siNET patients undergoing emergency surgery are consistent with findings from numerous studies highlighting worse outcomes after emergency surgery for gastrointestinal malignancies.^{13,14,15,30,31} In this study, emergency patients tended to be older, to have higher rates of CHD and distant metastases and tended to have larger tumors. Although these differences were not statistically significant, they indicate important trends regarding factors potentially influencing outcome differences between the two surgery cohorts. Age, CHD, UICC stage IV, and tumor size have previously been reported to negatively influence oncological outcome in siNET,^32–36 indicating vulnerable patient groups that require vigilant monitoring. Multivariable analysis revealed an association between emergency surgery and OS even after adjustment for the known confounders age and overall health status. Consistent with the findings of Folkestad et al., no significant association between emergency indication and PFS was revealed after adjustment for T3/T4 stage, N1 stage, and distant metastasis.³ These results suggest that the effect of emergency indication on — at least — PFS was confounded by, for example, advanced disease (UICC stage IV). In addition, other unknown confounding variables not included in this study must be considered. Further research with larger study cohorts is needed to identify additional prognostic factors for siNET prognosis.

Interestingly, nearly 50% of the emergency siNET patients had a preoperative NET diagnosis with recommended surgical therapy in most of these patients. About 78% (n = 14) of these patients had stage IV disease. Currently, surgery is recommended for unresectable advanced disease to prevent emergency conditions such as bowel obstruction or ischemia.^9,10 Obviously, timing of surgery in these patients is of utmost importance. Preoperative surveillance to identify, for example, increasing sub-ileus conditions should be thoroughly performed.

Although patients with siNET have a relatively good prognosis, identification of risk factors for adverse outcome is of paramount importance for appropriate postoperative treatment and follow-up management. The presented data suggest an association between emergency surgery and poorer outcome, even after complete tumor resection. Current guidelines recommend follow-up examinations every 6–12 months in G1/G2 siNET patients after curative resection and every 3–6 months after debulking surgery.¹⁹ Based on this study, closer follow-up of siNET patients after emergency surgery, including low-threshold indications for adjuvant therapy, should be discussed and encouraged.

The poorer survival of siNET patients undergoing emergency surgery, may stem from limited surgical radicality in the emergency setting. Achieving adequate oncological resection, including systematic LAD for siNET, is challenging and requires significant surgical experience. Despite fewer right hemicolectomies and more secondary completion surgeries in emergency cases, there were no differences in systematic LAD or R status. However, extended resection and completion surgery did not affect OS or PFS, suggesting these factors do not explain the outcome differences. Similarly to the findings of Manguso et al., this study noted fewer resected lymph nodes in the emergency cohort, although the number of positive lymph nodes was comparable.⁷ However, with 15 and 10 resected lymph nodes in the respective groups, the numbers of resected lymph nodes were above the established threshold for adequate systematic LAD.^9,37

This study has limitations. First, the study cohort is relatively small, although comprising 165 patients, which is substantial for a single-center study given the rarity of the disease. Second, this study was retrospective in nature. While prospective multicenter studies are necessary to elucidate oncological outcome and prognostic factors in siNET, well-conducted retrospective studies with comprehensive follow-up data may still provide valuable insights. This is particualary relevant for investigating the impact of emergency surgery in siNET, as randomized trials are not feasible. Despite including multivariable analysis to mitigate confounding effects of emergency verus elective surgery, residual unmeasured, and unknown confounding cannot be completely excluded.

Based on the results, emergency surgery correlated with poorer oncological outcome. Increased awareness for siNET is crucial to reduce diagnostic delays. Once diagnosed, identifying and monitoring patients at risk for emergency surgery is essential to prevent NET-associated complications and the need for emergency surgery.

Supplemental Material

sj-docx-1-sjs-10.1177_14574969241271841 – Supplemental material for Emergency surgery influences oncological outcome in small intestinal neuroendocrine tumors

Supplemental material, sj-docx-1-sjs-10.1177_14574969241271841 for Emergency surgery influences oncological outcome in small intestinal neuroendocrine tumors by Frederike Butz, Leonie Supper, Lisa Reinhard, Agata Dukaczewska, Henning Jann, Uli Fehrenbach, Charlotte Friederike Müller-Debus, Tatiana Skachko, Johann Pratschke, Peter E. Goretzki, Martina T. Mogl and Eva M. Dobrindt in Scandinavian Journal of Surgery

Footnotes

Author contributions

Frederike Butz: Study conception and design, Acquisition of data, Analysis and interpretation of data, Drafting of manuscript, Critical revision of manuscript.

Leonie Supper: Acquisition of data, Critical revision of manuscript.

Lisa Reinhard: Acquisition of data, Analysis and interpretation of data, Critical revision of manuscript.

Agata Dukaczewska: Study conception and design, Critical revision of manuscript.

Henning Jann: Study conception and design, Critical revision of manuscript.

Uli Fehrenbach: Study conception and design, Critical revision of manuscript.

Charlotte Friederike Müller-Debus: Study conception and design, Critical revision of manuscript.

Tatiana Skachko: Study conception and design, Critical revision of manuscript.

Johann Pratschke: Study conception and design, Critical revision of manuscript.

Peter E. Goretzki: Study conception and design, Critical revision of manuscript.

Martina T. Mogl: Study conception and design, Analysis and interpretation of data, Drafting of manuscript, Critical revision of manuscript.

Eva M. Dobrindt: Study conception and design, Analysis and interpretation of data, Drafting of manuscript, Critical revision of manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Frederike Butz

Martina T. Mogl

Supplemental material

Supplemental material for this article is available online.

References

Dasari

Shen

Halperin

, et al: Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:1335–1342.

Pape

Berndt

Müller-Nordhorn

, et al: Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2008;15(4):1083–1097.

Folkestad

Wasmuth

Mjønes

, et al: Survival and disease recurrence in patients operated for small intestinal neuroendocrine tumors at a referral hospital. Surg Oncol 2020;35:336–343.

Pantongrag-Brown

Buetow

Carr

, et al: Calcification and fibrosis in mesenteric carcinoid tumor: CT findings and pathologic correlation. AJR Am J Roentgenol 1995;164(2):387–391.

Laskaratos

Mandair

Hall

, et al: Clinicopathological correlations of mesenteric fibrosis and evaluation of a novel biomarker for fibrosis detection in small bowel neuroendocrine neoplasms. Endocrine 2020;67(3):718–726.

Laskaratos

Diamantopoulos

Walker

, et al: Prognostic factors for survival among patients with small bowel neuroendocrine tumours associated with mesenteric desmoplasia. Neuroendocrinology 2018;106(4):366–380.

Manguso

Gangi

Nissen

, et al: Long-term outcomes after elective versus emergency surgery for small bowel neuroendocrine tumors. Am Surg 2018;84:1570–1574.

Le Roux

Lombard-Bohas

Delmas

, et al: Relapse factors for ileal neuroendocrine tumours after curative surgery: A retrospective French multicentre study. Dig Liver Dis 2011;43(10):828–833.

Partelli

Bartsch

Capdevila

, et al: ENETS consensus guidelines for standard of care in neuroendocrine tumours: Surgery for small intestinal and pancreatic neuroendocrine tumours. Neuroendocrinology 2017;105(3):255–265.

10.

Niederle

Pape

Costa

, et al: ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology 2016;103(2):125–138.

11.

Jadoon

Khan

RMI

Khan

, et al: Comparative study of wound infection between elective and emergency abdominal surgeries: A retrospective cohort study. Ann Med Surg (Lond) 2023;85(5):1490–1495.

12.

Sæter

Fonnes

Rosenberg

, et al: Mortality after emergency versus elective groin hernia repair: A systematic review and meta-analysis. Surg Endosc 2022;36(11):7961–7973.

13.

Ogawa

Miyamoto

Harada

, et al: Evaluation of clinical outcomes with propensity-score matching for colorectal cancer presenting as an oncologic emergency. Ann Gastroenterol Surg 2022;6(4):523–530.

14.

Zhou

Jin

Wang

, et al: Comparison of short-term surgical outcomes and long-term survival between emergency and elective surgery for colorectal cancer: A systematic review and meta-analysis. Int J Colorectal Dis 2023;38:41.

15.

Esswein

Ninkovic

Gasser

, et al: Emergency resection is an independent risk factor for decreased long-term overall survival in colorectal cancer: A matched-pair analysis. World J Surg Oncol 2023;21:310.

16.

Brierley

Gospodarowicz

Wittekind

TNM Classification of Malignant Tumours. John Wiley & Sons, Hoboken, NJ, 2017.

17.

Ohrvall

Eriksson

Juhlin

, et al: Method for dissection of mesenteric metastases in mid-gut carcinoid tumors. World J Surg 2000;24(11):1402–1408.

18.

Clavien

Barkun

de Oliveira

, et al: The Clavien-Dindo classification of surgical complications: Five-year experience. Ann Surg 2009;250(2):187–196.

19.

Knigge

Capdevila

Bartsch

, et al: ENETS consensus recommendations for the standards of care in neuroendocrine neoplasms: Follow-up and documentation. Neuroendocrinology 2017;105(3):310–319.

20.

Eisenhauer

Therasse

Bogaerts

, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247.

21.

Concato

Peduzzi

Holford

, et al: Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol 1995;48:1495–1501.

22.

Peduzzi

Concato

Feinstein

, et al: Importance of events per independent variable in proportional hazards regression analysis. J Clin Epidemiol 1995;48(12):1503–1510.

23.

Turnbull

Tangel

Goldstein

PA.

Predictive value of emergency designation on outcomes of moribund patients. Cureus 2022;14(7):e26875.

24.

Manguso

Johnson

Harit

, et al: Prognostic factors associated with outcomes in small bowel neuroendocrine tumors. Am Surg 2017;83:1174–1178.

25.

Daskalakis

Karakatsanis

Stålberg

, et al: Clinical signs of fibrosis in small intestinal neuroendocrine tumours. Br J Surg 2017;104(1):69–75.

26.

Slott

Langer

Moller

, et al: Outlook for 615 small intestinal neuroendocrine tumor patients: Recurrence risk after surgery and disease-specific survival in advanced disease. Cancers (Basel) 2024;16:204.

27.

Jann

Roll

Couvelard

, et al: Neuroendocrine tumors of midgut and hindgut origin: Tumor-node-metastasis classification determines clinical outcome. Cancer 2011;117:3332–3341.

28.

Deguelte

Perrier

Hammoutene

, et al: Surgery and perioperative management in small intestinal neuroendocrine tumors. J Clin Med 2020;9:2319.

29.

Eriksson

Garmo

Hellman

, et al: The influence of preoperative symptoms on the death of patients with small intestinal neuroendocrine tumors. Ann Surg Oncol 2017;24(5):1214–1220.

30.

Becerra

Aquina

, et al: Emergent colectomy is independently associated with decreased long-term overall survival in colon cancer patients. J Gastrointest Surg 2017;21(3):543–553.

31.

Littlechild

Junejo

Simons

, et al: Emergency resection surgery for colorectal cancer: Patterns of recurrent disease and survival. World J Gastrointest Pathophysiol 2018;9:8–17.

32.

Lemelin

Maucort-Boulch

Castel-Kremer

, et al: Elderly patients with metastatic neuroendocrine tumors are undertreated and have shorter survival: The LyREMeNET study. Neuroendocrinology 2020;110:653–661.

33.

Sackstein

O’Neil

Neugut

, et al: Epidemiologic trends in neuroendocrine tumors: An examination of incidence rates and survival of specific patient subgroups over the past 20 years. Semin Oncol 2018;45(4):249–258.

34.

Norlén

Stålberg

Öberg

, et al: Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 2012;36(6):1419–1431.

35.

Kim

Warner

Roayaie

, et al: Revised staging classification improves outcome prediction for small intestinal neuroendocrine tumors. J Clin Oncol 2013;31:3776–3781.

36.

Pape

Jann

Muller-Nordhorn

, et al: Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008;113:256–265.

37.

Landry

Lin

Phan

, et al: Resection of at-risk mesenteric lymph nodes is associated with improved survival in patients with small bowel neuroendocrine tumors. World J Surg 2013;37(7):1695–1700.

Supplementary Material

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