Factors Affecting Survival Outcomes in Neuroendocrine Tumor of the Appendix over the Past Two Decades

Background: Appendiceal neuroendocrine tumors (NETs) rank as the third most frequent neoplasm affecting the appendix, originating from enterochromaffin cells. This study aims to evaluate the influence of various prognostic factors on the mortality rates of patients diagnosed with NETs of the appendix. Methods: Conducted retrospectively, the study involved 3346 patients, utilizing data sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis centered on investigating demographic characteristics, clinical features, overall mortality (OM), and cancer-specific mortality (CSM) among the cohort. Variables showing a p-value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox regression analysis. A Hazard Ratio (HR) > 1 indicated an unfavorable prognosis. Results: In the multivariate analysis, higher OM and CSM were observed in males, older age groups, tumors with distant metastasis, poorly differentiated tumors, and those who underwent chemotherapy. Non-Hispanic Black individuals showed elevated mortality rates. Conclusion: Delayed diagnosis may contribute to the increased mortality in this community. Improved access to healthcare and treatment is crucial for addressing these disparities. Larger prospective studies are needed to pinpoint the underlying causes of elevated mortality in non-Hispanic Black populations, and randomized controlled trials (RCTs) are warranted to evaluate therapies for advanced-stage appendix NETs.


Introduction
Appendiceal tumors are rare tumors, often diagnosed incidentally during appendectomies.These tumors are further classified as epithelial and non-epithelial tumors.The non-epithelial appendiceal tumors include lymphomas and appendiceal neuroendocrine tumors (aNETs) [1].aNETs are the most common tumors of the appendix and account for 0.5-1% of intestinal tumors [2].More than 80% of the cases of aNETs are diagnosed incidentally [3].These tumors are island-like or tubular carcinoids that originate from neuroendocrine cells [1].In recent decades, neuroendocrine tumors of the appendix have become more common due to improvements in the classification system, the presence of more developed imaging modalities, and a better understanding of the pathophysiology of these tumors [4].The majority of the cases of aNETs are diagnosed in adults between the ages of 20-50 years [5].These tumors are more common in women as compared to men, primarily due to a higher rate of incidental appendectomies in females who go through pelvic surgery [6].The presence of aNETs does not present any symptoms; therefore, these tumors do not have a specific clinical description (5).Macroscopically, these tumors are whitish nodules and can be either irregular or well-demarcated in appearance [7].After the incidental diagnosis of neuroendocrine tumors in the appendix, some additional tests are performed, which include endoscopy, biochemical tests, nuclear medicine imaging, and conventional imaging tests [8].Circulating biomarkers are also used to diagnose aNETs; however, this method is not used for tumors that are unable to produce serotonin.This diagnostic procedure also does not work for patients who do not have carcinoid features [9].
The most promising treatment for a neuroendocrine tumor of the appendix is surgery.The surgical procedure can involve simple appendectomy or right hemicolectomy (RHC).After the incidental discovery of a neuroendocrine tumor in the appendix, the next step is to decide whether appendectomy is sufficient or right hemicolectomy is required to dissect the lymph node to prevent the chances of reoccurrence [10,11].Several factors are considered before the treatment of a neuroendocrine tumor of the appendix.The size of the tumor is an important factor in deciding the extent of surgery.The size at which more complicated surgery is required is still controversial [12].aNETs smaller than 20 mm can be eliminated by simple appendectomy and have less chance of recurrence and metastasis.If the tumor is larger than 20 mm, more aggressive interventions are required for its treatment [1].Lympho-vascular invasion is another significant factor for the treatment of aNETs.It is an independent risk factor for the involvement of lymph nodes at right hemicolectomy [13].Samples should be prepared carefully because certain artifacts can contribute to the overestimation of lympho-vascular invasion during analysis [14].The location of the tumor is another parameter to decide the extent of surgery for patients with appendiceal neuroendocrine tumors [15].Liver-directed therapy is another treatment option for metastatic aNETs.The dominant metastasis sites for aNETs are the liver and regional lymph nodes.Liver-directed therapy is recommended for patients in which tumors are metastatic to the liver and surgical procedures are not feasible.However, prospective and retrospective trials for this therapy are very limited [16][17][18].A novel therapy to treat aNETs is radiolabeled somatostatin analog therapy [19].Other therapies include targeted therapies and cytotoxic chemotherapy [20,21].The prognosis of aNETs is generally good, and the survival rate is 5 years in more than 90% of the cases [1].Follow-up depends on the type of surgery and the features of the tumor.Although mortality is low for aNETs, they impact the quality of life of the patients.Therefore, proper management is crucial for the patients with aNETs [12].
Currently, there is a paucity of data regarding factors that determine the survival outcomes in patients suffering from aNETs.Therefore, the present study aimed to explore the factors that affect the survival outcomes in the patients who have aNETs over the past two decades.

Materials and Methods
A retrospective cohort study of patients with neuroendocrine tumors of the appendix was carried out using the Surveillance, Epidemiology, and End Results (SEER) database, which includes data from 18 registries and the November 2020 submission (http://www.seer.cancer.gov),accessed on 9 March 2024.The study comprised data on patients from the years 2000-2017.The SEER database is supported by the United States National Cancer Institute (US NCI).The SEER Program, known for being one of the most comprehensive and credible cancer data sources in the United States, compiles the SEER 18 database.This database records cancer incidence, as well as clinical and pathological details of patients and survival outcomes from 18 population-based cancer registries, encompassing roughly 28% of the US population.Data from the SEER database were retrieved using histological codes for the diagnosis of neuroendocrine tumor (NET) along with the primary site code corresponding to the appendix.Patients with an unspecified age at diagnosis, race, or stage of neuroendocrine tumor (NET) of the appendix development were excluded from the study.In this study, all the variables considered were treated as the primary exposures.
Overall mortality (OM) refers to deaths from any cause by the end of this study period.Cancer-specific mortality (CSM) is defined as deaths resulting from complications associated with neuroendocrine tumors (NETs) of the appendix by the study's conclusion.Variables extracted for the study included age at diagnosis, gender, race (White, Black, and others), ethnicity (non-Hispanic and Hispanic), tumor grade, stage at diagnosis (localized, regional, distant), residential geographic area, annual income, marital status, year of diagnosis, and treatment methods, such as surgery, radiation, and chemotherapy.
The Cox proportional hazards regression model presupposes that hazard rates stay consistent over time.In the analysis, variables showing a p-value below 0.1 in the univariate Cox regression were selected for inclusion in the multivariate Cox proportional hazards model.This approach was used to identify independent predictors of overall mortality (OM) and cancer-specific mortality (CSM), where a hazard ratio (HR) exceeding 1 indicates detrimental prognostic factors.All evaluations were two-tailed, employing a 95% confidence interval, and findings with a p-value under 0.01 were considered to be statistically significant.These statistical assessments were conducted using the STATA 18 software.

Discussion
The study analyzed 3346 US patients diagnosed with neuroendocrine tumors of the appendix between 2000 and 2017.Demographic analysis revealed a predominance of females, individuals aged 40-59, non-Hispanic Whites, residents in populous counties, and those with higher incomes.Most tumors were well-differentiated and at localized stages.Crude and multivariate analyses identified several significant factors affecting overall and cancer-related mortality.We discovered significant associations indicating a poor prognosis for patients with poorly differentiated tumors, advanced age, and advanced tumor stages.Specifically, poorly differentiated tumors exhibited substantially higher hazard ratios for both overall mortality and cancer-related mortality, suggesting a more aggressive disease course.Additionally, advanced age groups, particularly those aged 60 and above, demonstrated increased risks for mortality outcomes.Moreover, we observed higher OM and CSM rates among non-Hispanic Black individuals compared to other racial groups, indicating racial disparities in survival outcomes.
The available literature on NET, particularly those of the gastrointestinal (GI) tract and appendix, remains sparse, with limited long-term follow-up data and survival analyses.Epidemiological information, clinical presentations, and natural history of NET are largely derived from registry databases, lacking detailed clinical insights.A retrospective survey conducted across 13 Italian referral centers enrolled 820 patients with thoracic, gastroenteropancreatic (GEP), or metastatic NET of unknown primary origin (U-NET).Results showed a linear increase in NET incidences from 1990 to 2007, with pancreas and lung being the most common primary sites.The mean age at diagnosis was 60 years, though significantly earlier in patients with multiple endocrine neoplasia type 1 (MEN1).Symptoms varied, with tumor burden being the most common presentation, followed by endocrine syndromes and fortuitous diagnoses.Hormonal hypersecretions, notably insulin and serotonin, were prevalent.Advanced tumor stages were more frequent in GI and thymic NET [22].
In the study by Lewkowicz et al. (2015) focusing on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), clinical characteristics and factors influencing 5-year survival were investigated in 122 patients diagnosed between 2002 and 2011 in Kraków or its administrative region.The most common primary tumor sites were the small intestine, pancreas, rectum, stomach, appendix, and colon.Tumor differentiation varied, with most cases being well-differentiated.Notably, higher tumor grade (NEN G2), advanced stage according to the AJCC/UICC classification, and the presence of metastases at diagnosis were associated with poorer prognosis in univariate analysis.However, in multivariate analysis, advanced stage and the presence of metastases at diagnosis emerged as independent risk factors for death.Overall, 5-year survival was 85%, highlighting the importance of early detection and aggressive management in patients with GEP-NENs, particularly those presenting with advanced stage or metastases.This single-center study provides valuable insights for identifying patients with poorer prognoses who may benefit from a more intensive treatment approach [24].
Garcia-Carbonero et al. ( 2010) conducted a study utilizing data from a National Cancer Registry to explore GEP-NENs in Spain.The group studied included 907 tumors, largely comprising carcinoids, pancreatic nonfunctional tumors, metastatic NETs with no identifiable primary origin, insulinomas, and gastrinomas.Significant variations in the stage at diagnosis were observed and were influenced by factors such as gender, the location of the primary tumor, tumor type, and grade.The overall five-year survival rate stood at 75.4%, with more favorable outcomes in women, younger individuals, patients exhibiting hormonal syndromes, and those with tumors that were either early-stage or of a lower grade.Importantly, the stage and Ki-67 index were the sole independent variables found to predict survival, emphasizing their critical role in prognosis evaluation [25].
The study by Shen et al. focused on examining racial disparities in the incidence and survival rates among patients with neuroendocrine tumors (NETs).Their analysis revealed that Black individuals exhibited higher incidence rates of NETs across all stages, with the greatest disparity observed in the local stage compared to Whites.Moreover, despite exhibiting clinical characteristics generally linked to a better prognosis, Black patients with advanced-stage NETs had poorer survival outcomes.This research underscored substantial negative differences in socioeconomic and sociodemographic factors among Black patients, indicating that social determinants, support systems, and healthcare accessibility might play a role in the noted disparities in NET incidence and survival rates across different racial groups [26].
Contrary to previous findings, Goksu et al. conducted a study utilizing the SEER database to investigate the impact of race and ethnicity on disease characteristics and survival outcomes in gastrointestinal NETs, including appendiceal NETs.Analyzing data from 26,399 patients diagnosed between 2004 and 2015, they found significant differences in patient demographics and tumor characteristics among racial and ethnic groups.In particular, non-Hispanic White patients tended to be male, over the age of 60, and more frequently diagnosed with metastatic disease compared to Hispanic and non-Hispanic Black patients.Notably, Hispanic patients demonstrated better overall survival rates, whereas non-Hispanic Black patients showed improved cause-specific survival rates when compared to their non-Hispanic White counterparts.These findings were confirmed in multivariable analysis, indicating that race and ethnicity serve as independent prognostic factors in patients with gastrointestinal NETs [27].
In our research, the mortality rate was higher among patients diagnosed with appendix neuroendocrine tumors (NETs) who underwent chemotherapy compared to those who did not, likely due to chemotherapy administration to patients with metastatic disease [2].However, small-scale studies focusing on non-pancreatic NET patients treated with dacarbazine chemotherapy did not demonstrate improved survival outcomes [28,29].Limited data exist regarding chemotherapy effectiveness in appendix NETs, although multiple clinical trials are investigating mTOR inhibitors, tyrosine kinase inhibitors, and angiogenesis inhibitors for metastatic NETs [20].Everolimus, an mTOR inhibitor, has been evaluated for gastropancreatic NETs [30], while sunitinib, a tyrosine kinase inhibitor targeting VEGF, has been approved for metastatic pancreatic cancer treatment [2].Surufatinib, an oral multikinase inhibitor inhibiting VEGF, is in phase III clinical trials for extrapancreatic NET treatment [31].
Our study revealed that nearly all patients underwent surgical intervention.According to the National Comprehensive Cancer Network (NCCN), simple appendicectomy is recommended as the primary treatment for localized appendix NETs less than 2 cm [32,33].Tumors sized between 1.0 and 1.9 cm have a higher likelihood of nodal metastasis; however, studies indicate that right hemicolectomy does not confer benefits for these patients, with such intervention reserved for tumors exceeding 2 cm in size [33].Surgical excision for metastatic NET tumors may still be considered, particularly for patients with symptomatic liver metastases, aiming to alleviate symptoms [16].Newer guidelines show that simple appendicectomy would suffice for tumors less than the size of 1 cm and right hemicolectomy may be warranted for tumors > 2 cm.However, surgery for tumors 1-2 cm is still controversial, especially tumors with high-risk features [2].
Our findings suggest that poorly differentiated tumors are associated with increased mortality due to their aggressive nature and tendency to present with metastatic disease at diagnosis [7,34].
Our study was conducted on a large sample size of 3346 patients with tissue diagnosis of NET of the appendix.The patient population was selected with strict inclusion and exclusion criteria.However, our studies have weaknesses as it is a retrospective study, and the SEER database does not take into account other comorbidities or the type of surgery or chemotherapy the patient received.Furthermore, reasons for delayed treatment and/or diagnosis are not provided.

Conclusions
In conclusion, our study's findings demonstrate the impact of several factors, including race, age, tumor stage, and treatment modalities, on the survival outcomes in patients with NETs of the appendix.We found that people diagnosed at older ages, those receiving chemotherapy, and patients with advanced grades, distant stages, or poorly differentiated NETs have a higher risk of both OM and CSM.In terms of contributing factors, males and non-Hispanic Black individuals exhibited higher mortality rates, highlighting potential disparities in care.Given that these tumors are rare and often found as incidental findings, our results may represent a delay in diagnosis and should prompt the medical practice to be more familiar with the pathophysiology/clinical manifestations of these tumors as a way to increase the rate of diagnosis and, thus, improve patient outcomes and prognosis.These findings align with the existing literature on NETs by reinforcing the understanding that factors such as age at diagnosis, tumor grade, and stage significantly impact patient outcomes.This comprehensive study on neuroendocrine tumors (NETs) of the appendix, alongside auxiliary research, provides critical insights into refining precision medicine, enhancing medical quality, and ensuring patient safety, which are pivotal in the context of healthcare provision.By advocating for personalized treatment plans tailored to tumor specifics and patient demographics and promoting the use of genetic profiling, healthcare providers can significantly improve the prognosis for patients with NETs.Previous studies have also noted the increased mortality risk associated with advanced grades and stages of NETs, as well as the potential benefits of personalized treatment approaches.This study also points to the need for further research to elucidate the underlying causes of racial disparities and to identify optimal treatment strategies for different patient subgroups.Genetic factors may predispose non-Hispanic Black communities and males to have higher mortality, as seen in our study; however, larger prospective studies to identify the causes of this correlation are needed.The information provided in our study can be used as a point of reference to design further investigations, including but not limited to randomized controlled trials (RCTs) needed to enlighten treatment options or guidelines to redirect the approach and management of NETs.Our study paves the way for physicians to identify these ethnic groups who have higher mortality from NETs of the appendix and provide them with earlier screening and treatment to improve survival outcomes.

Table 2 .
Crude analysis of factors associated with all-cause mortality and cancer-related mortality among US patients diagnosed with neuroendocrine tumor of the appendix between 2000 and 2017.

Table 3 .
Multivariate Cox proportional hazard regression analyses of factors affecting all-cause mortality and cancer related mortality among US patients diagnosed with Neuroendocrine tumor of the appendix between 2000 and 2017.