The Clinicopathological Characteristics and Surgical Treatment of Gastrointestinal Neuroendocrine Neoplasm—A 10-Year Single-Center Experience

Background: Gastrointestinal neuroendocrine neoplasms (GI-NENs) represent a diverse group of tumors, with surgical resection being the gold standard for treatment. Materials and Methods: A retrospective analysis was conducted on 63 patients (32 women, 31 men) who underwent surgery for GI-NENs at the Department of Digestive Tract Surgery from January 2013 to June 2023. Tumors were classified by stage (localized, regionally advanced, metastatic). Results: Clinical symptoms were reported by 42 (66.7%) patients, with abdominal pain being the most common symptom, affecting 28 (44.4%) patients. The majority of tumors (44, 69.8%) originated in the midgut. The most frequently performed surgery was right hemicolectomy, carried out on 33 (52.4%) patients. Radical tumor resection was performed in 35 (55.6%) patients. Postoperative complications occurred in 12 (19%) patients, with male gender identified as an independent predictive factor for complications (p = 0.04). Non-functioning tumors were more common (33, 52.4%), and most tumors were classified as grade 1 histopathologically (49, 77.8%). Distant metastases were present in 29 (46%) patients. The overall two-year survival rate was 94.9%, with a five-year survival rate also estimated at 94.9%. Conclusions: GI-NENs are often diagnosed at advanced stages, frequently with distant or lymph node metastases, and predominantly arise in the midgut. Despite low postoperative morbidity and mortality, male gender may be a predictor of postoperative complications. Overall, the prognosis for GI-NENs is favorable, reflected in high overall survival rates.

Initially considered rare since their discovery in 1867, the incidence of NENs has increased significantly, from 1.09 per 100,000 in 1973 to 6.98 per 100,000 in 2012 [4].This rise is attributed to advancements in diagnostics and healthcare.Currently, NENs represent 0.5% of all malignant neoplasms and 2% of malignant GI tumors [5].Geographic and demographic variations in the incidence of GI-NENs have been observed, with the highest rates reported in North America and Europe, where small intestinal and colonic NENs are predominant.Conversely, in Asia, rectal neuroendocrine neoplasms are the most prevalent [4,6].The incidence of GI-NENs increases with age, peaking around the sixth decade of life [6].
Currently, there is no universally accepted biomarker for GI-NENs.Chromogranin A (CgA) is one of the most commonly used biomarkers, but its specificity is often limited.Although CgA levels correlate with tumor mass, they can be elevated in various other conditions, which reduces their diagnostic utility [12][13][14][15][16].For patients suspected of having hormonally active GI-NENs, biomarkers such as serotonin, gastrin, norepinephrine, and corticotropin can provide diagnostic clues but often lack precision.These biomarkers are primarily useful for specific tumor types with well-defined clinical syndromes [12,13].
Advances such as the NETest, which uses mRNA profiling, have shown promise in improving diagnostic accuracy, with sensitivity and specificity nearing 99%.However, the NETest has not yet been widely adopted [17,18].
Given these challenges, endoscopic biopsy remains the gold standard for diagnosing NENs in the stomach, duodenum, and colorectum [19].For small intestinal NENs, videocapsule endoscopy and double-balloon endoscopy (DBE) are effective alternatives, with DBE demonstrating high sensitivity for detecting primary lesions.Computed tomography (CT) and magnetic resonance imaging (MRI) are essential for staging, with MRI being more effective in detecting liver and bone metastases.For functional imaging, 68Ga-DOTATATE PET/CT is preferred due to its superior sensitivity and specificity for somatostatin receptorexpressing tumors [6].
Tumor resection is the gold standard for the treatment of GI-NENs, as the radical resection of the tumor is the only curative option for patients.Currently, both endoscopic and surgical resections can be performed.Endoscopic resection is recommended only for small (usually less than 1 or 2 cm) well-differentiated NENs in the stomach, duodenum, and rectum.On the other hand, surgical resection is the first line of treatment for small bowel and colon NENs, as well as for more advanced and larger tumors of the stomach, duodenum, and rectum [19].However, at the time of diagnosis, over 60% of patients have an unresectable tumor or regional or distant metastases; thus, only palliative surgery is possible [23].Recent studies have shown that aggressive surgical cytoreduction increases overall survival (OS) in patients with NENs, regardless of the tumor stage [24].Therefore, it is crucial to consider appropriate surgical treatment in each case, taking into account the tumor's location and stage, as well as the patient's clinical status [25,26].
In cases of advanced or metastatic GI-NENs, medical treatments including somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) are crucial.SSAs are effective in controlling symptoms and slowing disease progression in well-differentiated, somatostatin receptor-positive tumors.Additionally, the NETTER-1 trial has shown that PRRT significantly prolongs progression-free survival [27].On the other hand, systemic chemotherapy is reserved for more aggressive, poorly differentiated NECs and provides necessary options for managing these challenging cases [19,27].
The main aim of this study is a clinical characterization of GI-NENs and an analysis of the perioperative, short-, and long-term outcomes of the surgical treatment of GI-NENs based on data from the Department of Digestive Tract Surgery of the Medical University of Silesia in Katowice, Poland.

Study Design and Population
The study group consisted of 63 adult patients (32 women, 50.8%; 31 men, 49.2%), aged 30-84 years (mean age 59.7 years, SD 11.84), who underwent surgery for GI-NENs from January 2013 to June 2023 in the Department of Digestive Tract Surgery, Medical University of Silesia in Katowice, Poland.

Study Inclusion/Exclusion Criteria
Our retrospective analysis included patients from the Department of Digestive Tract Surgery at the Medical University of Silesia in Katowice, Poland, who were treated for GI-NENs.Before access, the patients' data were fully anonymized by the local medical archive.Electronic medical records were individually reviewed.We analyzed only the data of patients diagnosed with GI-NENs by a pathology specialist and who underwent primary surgical tumor resection.Recurrent GI-NENs and mixed adenoneuroendocrine carcinoma (MANEC) diagnosed in histopathology were excluded from the analysis.

Inclusion Criteria for Surgical Treatment
All patients were evaluated by a multidisciplinary team that included surgeons, radiologists, and oncologists, who determined the qualification for a particular type of surgical procedure based on computed tomography (CT) scans.Additionally, 47 patients (74.6%) underwent an endoscopic biopsy with a histopathological diagnosis of GI-NEN prior to surgical treatment.All procedures were performed according to ENETS Guidelines [28,29].
Cytoreduction was defined as the radical resection of the primary tumor in the presence of distant metastasis.
The cohort was divided into three subgroups according to tumor stage: localized (no lymph nodes or distant metastasis), regionally advanced (presence of lymph node metastasis without distant metastasis), and metastatic (presence of distant metastasis).
Overall survival (OS) was measured from the date of the surgical procedure to either the date of death or the date of the last contact.

Analyzed Data
The study analyzed various parameters related to the patients and their treatment outcomes.These parameters included patients' general characteristics, such as age, gender, and body mass index (BMI); clinical symptoms; American Society of Anesthesiologists (ASA) score; the type and duration of surgery; surgical margin status (categorized as R0 for no residual tumor, R1 for microscopic residual tumor, or R2 for macroscopic residual tumor); incidence of postoperative complications; reoperations; mortality; duration of hospitalization; rehospitalizations; as well as primary tumor localization, diameter, and released hormones.Additionally, selected pathological parameters were analyzed, including lymphovascular and perineural invasion, histopathological grading, mitotic index, cell proliferation index (Ki-67), lymph node and distant metastases, and follow-up.These parameters were thoroughly examined to gain insights into the clinical characteristics, treatment outcomes, and overall prognosis of patients with GI-NENs.

Statistical Analysis
The statistical analysis was performed using Statistica ® (Tulsa, OK, USA, 2013) software version 13.3 (StatSoft).Absolute values and percentages were used to present qualitative variables, while ranges, means, and standard deviations, or medians with interquartile ranges, were applied for quantitative variables.Predictive factors of postoperative complications were calculated using univariate logistic analysis.Variables identified as significant by univariate analysis were selected for multivariate analysis with logistic regression to identify independent predictors of postoperative complications after the surgical treatment of GI-NENs.Between-group comparisons were performed for two localization categories (foregut and midgut, as there was only one hindgut tumor), in terms of clinical symptoms, released hormones, tumor size, grading, metastases, and recurrence.The analysis was performed using the chi-square test, Fisher's exact test, or Mann-Whitney U test.Survival analysis was conducted using the Kaplan-Meier estimator, and prognostic factors were analyzed using the Cox proportional hazards regression model.In the survival analysis, patients who were lost to follow-up (3, 4.8%) were treated as censored data.A p-value < 0.05 was considered statistically significant.

General Patient and Tumor Characteristics
In the whole cohort, 42 patients (66.7%) reported clinical symptoms.The most common clinical symptom was abdominal pain, noted in 28 patients (44.4%), followed by carcinoid syndrome in 22 patients (34.9%) and weight loss in 15 patients (23.8%).Most of the tumors (44; 69.8%) were localized in the midgut, with the predominant localization being the ileocecal valve (31; 49.2%).

Hormones and Tumor Markers
In the whole group, 46 (73%) patients were hospitalized in the Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland before surgical treatment.During their hospitalization, hormonal plasma concentrations and tumor markers were evaluated.The results are shown in Table 4.No significant differences were observed between symptomatic and asymptomatic patients in terms of functional tumor and secreting hormones, as well as for most of the hormone and tumor marker levels.The only significant difference observed between symptomatic and asymptomatic patients was in gastrin plasma level (15.3 (0-120, IQR 24.5) pg/mL vs. 10 (0-36.2,IQR 10.2) pg/mL, p = 0.02).Nonetheless, none of the patients had a gastrin-secreting GI-NEN; in addition, the median gastrin levels (in symptomatic, asymptomatic, and total patients) were within normal ranges.Therefore, this finding might be coincidental and does not indicate a significant role for elevated gastrin levels in the symptomatology observed in this patient cohort (Table 5).Abbreviations: CA19.9-Carbohydrate antigen 19.9, CEA-Carcinoembryonic antigen, 5-HIAA-5-Hydroxy indoleacetic acid, SD-standard deviation, IQR-interquartile range.

Comparison between Foregut and Midgut GI-NENs
No statistically significant differences were observed between tumor stage and age or BMI.More patients reported nausea and vomiting in the localized tumor group compared to the regionally advanced and metastatic groups (4; 30.8% vs. 0; 0% vs. 0; 0%, p = 0.02).Additionally, more patients reported constipation in the localized tumor group compared to the regionally advanced and metastatic groups (2; 15.4% vs. 0; 0% vs. 0; 0, p = 0.04).These results are probably associated with the foregut localization of tumors in patients with nausea and vomiting.There was no statistically significant difference in the occurrence of other clinical symptoms, nor in the overall occurrence of clinical symptoms between groups (Table 7).Abbreviations: SD-standard deviation, IQR-interquartile range, BMI-body mass index, ASA-American Society of Anesthesiologists.

Survival Analysis
Median follow-up time was 24.4 (0.37-102, IQR 45.9) months.During the follow-up period, an additional 2 deaths occurred in patients with midgut-located tumors due to cancer cachexia.The two-year OS was 94.9%, while the estimated five-year survival was 94.9%.Additionally, there was no significant difference in two-year OS between localized, regionally advanced and metastatic NENs (100% vs. 90% vs. 96.4%,p = 0.46) (Figure 2).There were no significant differences in overall survival between patients in terms of age, gender, hormonal activity, preoperative medical treatment, tumor localization, tumor grading, distant metastasis, Ki-67 index, tumor diameter, lymphovascular invasion and scope of surgery (Table 10).Abbreviations: HR-hazard ratio, CI-confidence interval.
During the follow-up, one case of tumor recurrence (1.6%) was observed in a patient with gastric non-secreting neuroendocrine carcinoma (NEC), occurring 22 months after a proximal gastrectomy (Merendino procedure).

Discussion
GI-NENs are insidious tumors, often presenting with no clinical symptoms for extended periods.Raphael MJ et al. suggest that between 9% and 39% of neuroendocrine tumors in the gastrointestinal tract may be asymptomatic.In our study, 21 patients (33.3%) did not present any symptoms.Additionally, up to 87% of symptomatic patients may exhibit non-specific symptoms [30].Works in the literature report varying incidences of symptoms for GI-NENs: abdominal pain is observed in 28-79% of patients, followed by bowel obstruction (18-24%), diarrhea (10-32%), weight loss (2-58%), and gastrointestinal bleeding (4-10%) [30][31][32].In our cohort, abdominal pain was reported by 28 patients (44%), diarrhea by 12 patients (19%), and weight loss by 15 patients (23.8%).The absence of bowel obstruction and gastrointestinal bleeding in our study may be related to the lack of GI-NENs located in the distal colon and the presence of only one rectal tumor.These symptoms are often attributed to alternative diagnoses such as irritable bowel syndrome or dyspepsia [31].Consequently, the diagnosis of GI-NENs is frequently delayed by 5-7 years, by which time lymph node and/or distant metastases are often already present [2].
The specific symptom of functioning GI-NENs that release serotonin is carcinoid syndrome.This syndrome includes symptoms such as flushing, diarrhea, abdominal cramping, valvular heart disease, telangiectasia, wheezing, pellagra, and paroxysmal tachycardia.Additionally, mesenteric fibrosis can occur in patients with carcinoid syndrome, leading to acute symptoms such as intestinal obstruction and intestinal ischemia, which may require emergency treatment [33].Carcinoid syndrome is observed in approximately 6-20% of GI-NEN cases, with its incidence being primarily associated with metastatic tumors located in the midgut.This syndrome typically manifests when hormones produced by neuroendocrine tumor cells enter the systemic circulation, usually only after liver metastasis has developed and bypassed hepatic metabolism [31,34].
In our cohort, 22 patients (34.9%) exhibited carcinoid syndrome, with a higher prevalence among those with metastatic tumors (15 patients; 51.7%).This higher incidence in our study may be attributed to the fact that most metastatic tumors originated in the midgut compared to localized and regionally advanced tumors (25 patients; 86.2% vs. 9 patients; 69.2% vs. 10 patients; 47.6%).
Previous studies indicate that between 60% and 93% of gastrointestinal neuroendocrine neoplasms (GI-NENs) are metastatic at the time of diagnosis.The prevalence of lymph node metastases ranges from 14.3% to 34.7%, while distant metastases are reported in 17% to 79.1% of cases.Liver metastases are the most common, occurring in 56% to 84.7% of cases, and are frequently associated with GI-NENs located in the midgut (up to 71%) [29,31,35,36].In our cohort, 49 patients (77.8%) had lymph node or distant metastases.Specifically, lymph node metastases were present in 44 patients (69.8%), and distant metastases were found in 29 patients (46%).Among the distant metastases, most were located in the liver (23 out of 29).The discrepancy between the incidence of lymph node metastases in the literature (14.3% to 34.7%) and our study (69.8%) may be attributed to the high prevalence of midgut tumors in our cohort (44 patients; 69.8%),where metastases are reported in up to 71% of cases [29,31,35,36].
There are three main categories for surgical indications in the treatment of GI-NENs: radical or palliative tumor excision, cytoreduction (debulking) of the primary tumor, lymph nodes, or distant metastases, and palliative tumor resection aimed at alleviating symptoms such as obstruction, jaundice, gastrointestinal bleeding, or pain [43][44][45].In our cohort, radical tumor resection was performed in 35 patients (55.6%), cytoreduction in 28 patients (44.4%), and no patients (0%) received palliative treatment.Rothenstein et al. reported that 62.4% of patients underwent radical tumor resection and 26.6% underwent cytoreduction [37].The discrepancy in surgical scope between our study and Rothenstein's may be attributed to the higher proportion of metastatic tumors in our cohort.
The scope and type of surgical procedure for GI-NENs depend significantly on tumor location and staging.Radical resection (R0 resection) of the primary tumor is considered the optimal treatment approach [45].In our study, all procedures were performed with R0 resection, reflecting an intent to achieve complete tumor removal.For advanced tumors originating from the foregut, partial resection of the affected organ with additional lymphadenectomy may be required.In contrast, advanced neuroendocrine tumors of the midgut generally necessitate a more aggressive approach due to their poorer prognosis compared to other GI-NENs.Notably, the size of midgut tumors often does not correlate with their biological behavior, and metastases can be present even in small primary lesions.Segmental resection with wide lymphadenectomy is typically required for tumors in the jejunum, proximal, and middle ileum, while other midgut tumors may be managed with hemicolectomy and extensive lymphadenectomy.Hindgut tumors are generally treated similarly to foregut tumors [46][47][48].
In our cohort, the majority of patients had GI-NENs located in the midgut (44; 69.8%), with a notable concentration at the ileocecal valve (31; 49.2%).Consequently, the most frequently performed procedure was right hemicolectomy (33; 52.4%).Only 1 patient (1.6%) underwent a local tumor resection with curative intent for a locally advanced 7 mm duodenal tumor.
Regarding the management of distant metastases, particularly liver metastases, several treatment options are currently available.These include somatostatin analogues, mTOR inhibitors such as everolimus, and vascular endothelial growth factor (VEGF) inhibitors like bevacizumab.Additionally, invasive treatments such as metastasectomy, cytoreductive surgery, alcohol ablation, cryoablation, and radiofrequency ablation are also utilized.Somatostatin analogues help alleviate symptoms and exhibit antineoplastic effects, while both everolimus and bevacizumab have been shown to significantly improve progressionfree survival.For patients who are contraindicated for metastasis resection, ablation techniques-such as alcohol, cryo-, or radiofrequency ablation-can achieve complete or significant symptom response rates of up to 80% [23].Despite these available treatments, surgical intervention remains the gold standard for managing GI-NEN metastases, with a notable improvement in five-year survival rates, increasing from 61% to 81% [23].Research by Tierney et al. has demonstrated that resection of the primary tumor can be a predictive factor for prolonged overall survival [49].Therefore, whenever feasible, primary tumor resection should be pursued.In our study, 2 out of 29 patients (6.9%) underwent metastasectomy, while 18 out of 29 patients (62.1%) received systemic therapy with somatostatin analogues (16 out of 29; 55.2%) and chemotherapy (1 patient received EOX, and 1 patient received FOLFOX treatment).
Early postoperative complications were observed in 12 (19.1%)patients, with the highest incidence among those with localized tumors (5; 38.5%), compared to regionally advanced (5; 23.8%) and metastatic tumors (2; 6.9%).Postoperative mortality occurred in 2 (3.2%) patients, both with locally advanced neoplasms after pancreaticoduodenectomy.These results align with published data on the treatment of GI-NENs.Works in the literature report postoperative morbidity rates between 5.8% and 7.9%, and mortality rates ranging from 0.5% to 2% [50][51][52].For localized or regionally advanced tumors, morbidity rates vary between 0% and 39%, while mortality rates range from 0% to 6.9% [52,53].In our study, the independent predictive factor for postoperative complications was patient gender (male gender, p = 0.04, OR = 6.2, 95% CI = 1.1-35.5).Al-Taki et al. also identified gender as a predictive factor for postoperative complications, with female gender associated with a lower risk (p < 0.001, OR = 0.7, 95% CI = 0.69-0.71)[38].This suggests that women may have a lower risk of postoperative complications compared to men.The observed gender differences in preoperative risk factors might be related to males' tendency to engage less frequently with primary healthcare services, resulting in later-stage surgical interventions.Studies from Canada, the United States, and the United Kingdom have noted that males utilize primary healthcare services less often than females [49][50][51][52][53].
The main limitations of this study include its retrospective design and the fact that it was conducted at a single medical center.The small cohort size may limit the statistical power of the study and affect the robustness of the conclusions drawn.Additionally, the low number of hindgut tumors in the cohort may not provide a comprehensive representation of this tumor type, potentially affecting the generalizability of the findings.
The study also lacked a control group, which restricts the ability to compare outcomes against a non-treatment or alternative treatment group, and thereby limits the assessment of the relative efficacy of the interventions used.Furthermore, selection bias may be present due to the study being conducted at a single institution, which might not reflect the broader population of patients with neuroendocrine tumors.The impact of the COVID-19 pandemic, which resulted in limited access to medical care, could have delayed diagnoses for patients between 2020 and 2022, potentially leading to more advanced tumor stages and influencing the overall outcomes.These factors combined-small sample size, single-center design, lack of a control group, and pandemic-related delays-must be considered when interpreting the results and their applicability to other settings or broader populations.
Nonetheless, this study provides a comprehensive analysis of surgical outcomes and complications associated with GI-NENs in a well-defined cohort.One of its key strengths is the detailed examination of both intraoperative and postoperative complications, offering valuable insights into the surgical management of GI-NENs.The study's inclusion of a wide range of clinical and pathological parameters enhances the robustness of the findings, allowing for a nuanced understanding of factors influencing surgical outcomes.Additionally, the use of rigorous statistical analyses, including both univariate and multivariate logistic regression, strengthens the validity of the predictive factors identified for postoperative complications.The high rate of R0 resections and the thorough reporting of hormonal and tumor marker levels contribute to a detailed characterization of the disease.Despite the study's single-center nature, the data collected from a large cohort over an extended period provides a solid foundation for evaluating surgical strategies and outcomes in GI-NENs, thereby advancing the current understanding in this field.supervision, B.J., S.M.; project administration, B.J., S.M.All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Institutional Review Board Statement:
A retrospective study of patients' fully anonymized medical records was performed.The written consent for surgical treatment was obtained from all the participants.Surgical procedures were performed in accordance with the 1964 Declaration of Helsinki on Medical Research Involving Human Subjects and its amendments or comparable ethical standards.Based on the Polish Act of 5 December 1996, on the Profession of Medical Doctors and Doctors of Dental Medicine (Journal of Laws of 2023, item 1516 as amended), a retrospective data analysis of medical records is not considered a medical experiment and does not require evaluation by IRB.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Table 1 .
General characteristics of patients undergoing surgery due to gastrointestinal neuroendocrine neoplasms.

Table 3 .
Predictive factors of postoperative complications after surgical treatment of GI-NENs in univariate and multivariate logistic regression analysis.

Table 4 .
Hormone and tumor marker results for patients with GI-NENs.

Table 5 .
Occurrence of symptoms depending on the hormone and tumor marker levels in patients with GI-NENs.

Table 7 .
Patients' characteristics by stage of GI-NEN.

Table 8 .
Surgery characteristics by stage of GI-NEN.

Table 9 .
Tumor characteristics by stage of GI-NEN.

Table 10 .
Univariate analysis of factors with overall survival using Cox proportional hazards regression model.