Incidentally discovered, intentionally managed: a narrative review of the last decade’s updates on the management of neuroendocrine tumor of the appendix

Salvatore Raiaa,i, Maria Rita Gaia Livatinog, Giorgio Maria Orazig, Maria Grazia Marattab,i, Enza Gencod,i, Romina Grazia Giancipolih,i, Vittoria Rufinie,i, Ernesto Rossic, Sabrina Chiloroa, Claudio Fiorillof, Sergio Alfierif, Giampaolo Tortorab, Alfredo Pontecorvia, Guido Rindic,i, Antonio Bianchia,i*, Giovanni Schinzarib,i*

Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

aDepartment of Translational Medicine and Surgery, Section of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore (Salvatore Raia, Sabrina Chiloiro, Alfredo Pontecorvi, Antonio Bianchi); bDepartment of Translational Medicine and Surgery, Section of Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore (Mariagrazia Maratta, Giampaolo Tortora, Giovanni Schinzari); cDepartment of Women’s and Children’s Health and Public Health Sciences, Section of Anatomic Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore (Ernesto Rossi, Guido Rindi); dDepartment of Diagnostic Imaging and Oncologic Radiotherapy, Fondazione Policlinico Universitario A. Gemelli IRCCS (Enza Genco); eDepartment of Diagnostic Imaging and Oncologic Radiotherapy, Section of Nuclear Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS (Vittoria Rufini); fDepartment of Surgical Sciences, Section of Digestive Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS (Claudio Fiorillo, Sergio Alfieri), Rome, Italy; gUniversità Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (Maria Rita Gaia Livatino, Giorgio Maria Orazi); hPET-CT Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (Romina Grazia Giancipoli); iEuropean Neuro-Endocrine Tumor Society (ENETS) Center of Excellence, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (Salvatore Raia, Maria Grazia Maratta, Enza Genco, Romina Grazia Giancipoli, Vittoria Rufini, Guido Rindi, Antonio Bianchi, Giovanni Schinzari)

Correspondence to: Salvatore Raia, MD, Department of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy, e-mail: salvatore.raia1@unicatt.it

*Co-senior authors (shared last authorship)

Received 19 February 2026; accepted 21 March 2026; published online 28 May 2026
DOI: https://doi.org/10.20524/aog.2026.1070
© 2026 Hellenic Society of Gastroenterology

Abstract

Appendiceal neuroendocrine neoplasms (aNENs) represent an increasingly recognized and heterogeneous subset of gastroenteropancreatic neuroendocrine tumors (NETs), most often identified incidentally on appendectomy specimens. Postoperative management relies on accurate risk stratification grounded in histopathological assessment and aligned with major international guidelines (WHO, ENETS), which distinguish between well-differentiated NETs (NET grades 1 to 3) and poorly differentiated neuroendocrine carcinomas. Critical prognostic determinants shaping therapeutic decision-making include tumor size, proliferative index (Ki-67), depth of invasion—particularly mesoappendiceal involvement—and lymphovascular invasion (LVI). Consensus recommendations suggest simple appendectomy as definitive treatment for low-risk tumors (<1 cm) and right hemicolectomy for high-risk lesions (>2 cm) or those exhibiting LVI. However, the management of intermediate-sized aNENs (1.0-2.0 cm) remains the principal area of clinical uncertainty, with emerging data suggesting that appendectomy alone may be sufficient for carefully selected patients without adverse pathological factors. This review synthesizes and critically appraises the most recent evidence and international guidelines with the goal of refining current clinical practice. In particular, it provides an updated framework for individualized risk stratification, evaluates the balance between oncological benefit and procedural morbidity in determining the optimal surgical approach, and outlines evidence-based surveillance strategies to support a more consistent, risk-adapted multidisciplinary management of aNENs.

Keywords Appendiceal neuroendocrine tumor, neuroendocrine neoplasms, surgical management, right hemicolectomy, ENETS guidelines

Ann Gastroenterol 2026; 39 (4): 390-404

Introduction

Neuroendocrine neoplasms (NENs) represent a biologically and clinically heterogeneous group of tumors arising from the diffuse neuroendocrine cell system, with the gastroenteropancreatic (GEP) tract recognized as the principal site of origin, a point repeatedly underscored by leading international guidelines [1]. While general guidelines provide a comprehensive overview of diagnosis and treatment, the specific clinical approach often requires further refinement based on the primary site [2]. Within the GEP system, appendiceal NENs (aNENs) constitute a distinct and relatively rare entity, typically accounting for a small percentage of appendectomy specimens [3]. These tumors are frequently discovered incidentally during surgery for suspected acute appendicitis, initiating a complex postoperative management pathway [4].

Accurate management hinges on precise histopathological characterization and risk assessment. Current protocols that guide diagnostic and therapeutic procedures emphasize the pathological staging and grading based on morphology and proliferative index (Ki-67), distinguishing between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated carcinomas (NECs) [5]. The primary therapeutic challenge involves determining the optimal extent of surgical intervention, balancing the goal of complete tumor eradication with the morbidity associated with aggressive procedures such as right-sided hemicolectomy [6]. The decision-making process is highly refined, having been recently clarified by the latest guidance papers from leading NET societies [7].

Current clinical guidelines utilize a combination of key prognostic factors to determine the required surgical extent [7,8]. The main parameters used to stratify the risk of recurrence and nodal metastasis are tumor size, histological grade (G1-G3), depth of invasion (especially involvement of the mesoappendix), positive or uncertain resection margins, and the presence of lymphovascular invasion (LVI) [6,9]. A general consensus dictates simple appendectomy for low-risk tumors (<1 cm) and mandatory extended resection for high-risk tumors (>2 cm) [6,7].

Crucially, the management of intermediate-sized aNENs measuring 1.0-2.0 cm represents the most significant area of clinical controversy and therapeutic variability [10]. Recent data emphasize that, for selected patients in this size group, a conservative simple appendectomy may be considered definitive treatment if adverse pathological features are absent [10]. This necessitates a rigorous review of postoperative pathology to identify patients who truly benefit from the added morbidity and cost of reoperation [6]. Furthermore, the post-treatment phase presents unique challenges regarding the validation of standardized surveillance strategies. The cost-effectiveness and clinical utility of serum biomarkers, such as chromogranin A (CgA), and the role of routine cross-sectional imaging or somatostatin receptor imaging in the long-term followup of completely resected low-risk aNENs, remain an area of ongoing debate that lacks universally validated protocols [5].

In light of the continuous evolution in pathological classification, refined surgical risk stratification, and the need for standardized surveillance, this narrative review aims to provide a comprehensive and concise synthesis of the latest literature and major international guidelines. We focus on clarifying the contemporary multidisciplinary approach, translating the current evidence into a practical framework for the risk assessment, optimal surgical strategy, and recommended long-term surveillance protocols for aNENs. A summary of the current state of the art is provided in Fig. 1.

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Figure 1 State-of-the-art summary of aNETs (2025)

Overview of key domains in the contemporary understanding of aNETs, including epidemiology, etiopathogenesis, clinical presentation, histopathology, special populations, and outcomes. Most aNETs are incidentally detected, well-differentiated, localized neoplasms with excellent prognosis. Prognostic stratification is driven by tumor size, grade, lymphovascular invasion, and mesoappendiceal invasion. Special considerations apply to pediatric and pregnant patients, in whom appendectomy is generally sufficient and outcomes are favorable

ACTH, adrenocorticotropic hormone; aNEN, appendiceal neuroendocrine neoplasm; cm, centimeters; CNV, copy number variation; e.g., for example; ENETS, European Neuroendocrine Tumor Society; G1–G3, grade 1–grade 3; GCA, goblet cell adenocarcinoma; GCC, goblet cell carcinoma; GEP, gastroenteropancreatic; IHC, immunohistochemistry; INSM1, insulinoma-associated protein 1; Ki-67, Ki-67 proliferation index; LOH, loss of heterozygosity; LVI, lymphovascular invasion; MANEC, mixed adenoneuroendocrine carcinoma; MiNEN, mixed neuroendocrine–non-neuroendocrine neoplasm; miR, microRNA; N+, positive lymph nodes/nodal involvement; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; OS, overall survival; PNI, perineural invasion; RHC, right hemicolectomy; SATB2, special AT-rich sequence-binding protein 2; vs, versus; WHO, World Health Organization; yr/yrs, year/years

Materials and methods

This narrative review was conducted to provide a comprehensive and up-to-date synthesis of the literature regarding aNENs, focusing specifically on pathological classification, optimal surgical strategies, and long-term surveillance protocols. A targeted, non-systematic search of relevant publications was performed across the electronic databases PubMed/MEDLINE, Scopus and Google Scholar. The search was restricted to articles published from January 2015 up to November 2025 to ensure contemporary relevance. Search terms and MeSH headings used in various combinations included: “Appendiceal Neuroendocrine Neoplasm”, “aNEN”, “Appendiceal Carcinoid”, “Appendiceal NET”, “Right Hemicolectomy”, “Extended Resection”, “Lymphovascular Invasion”, “LVI”, “Goblet Cell Carcinoma”, “MANEC”, “Surveillance”, “Follow-up”, and “Risk Stratification”. This review is not a systematic review and did not follow PRISMA guidelines; instead, it was conducted as a narrative synthesis of the available literature, with studies selected based on clinical relevance, methodological quality, and contribution to current understanding of aNENs. No language-based exclusion criteria were applied during study selection. We prioritized the inclusion of major international clinical practice guidelines (e.g., ENETS, NANETS), systematic reviews and meta-analyses, and large-cohort original studies (including retrospective and registry-based analyses) that assessed epidemiology, prognostic factors, surgical outcomes and long-term survival. Publications such as single case reports, letters to the editor, and conference abstracts were generally excluded, unless they provided unique and critical information. Data from the included literature were critically reviewed and synthesized thematically into sections covering Epidemiology, Etiopathogenesis, Clinical Presentation, Histology/Diagnosis, and Outcome/Surveillance, to construct a practical and evidence-based clinical framework.

Epidemiology

The analysis of appendix tumor trends across population-based cohorts has demonstrated a conspicuous increase in incidence over time, consistent with the global epidemiological pattern for NENs [11]. As the most common primary site for NENs is the GEP tract [1], aNENs represent a different subset requiring site-specific clinical refinement [2]; therefore, the clinical management has to be defined according to the specific primary site of the tumor [3]. Early single-center series reported a prevalence of aNENs in approximately 0.2% of appendectomy specimens, occasionally noting a minor male predominance [4]. The majority of aNEN diagnoses typically occur in the 5th or 6th decade of life [5]. The increasing incidence of aNENs is a phenomenon attributed to diagnostic optimization [6]. The reported detection rate of aNENs in surgical specimens generally ranges from 0.2-0.9% [7], reinforcing the understanding that the appendix and small intestine collectively account for a high proportion of NENs arising from the GEP system [8]. ANENs are the most frequent primary tumor of the appendix [9], usually found incidentally and characterized by their small size [10]. This global increase in NEN incidence was confirmed by a large-scale cohort study in the USA (2000-2018), which reported a significant rise in age-adjusted incidence, with the most marked increases observed specifically in localized-stage and appendiceal tumors [12]. Enhanced precision was provided by the continuous monitoring of incidence and survival trends for gastrointestinal (GI) NENs through analyses of the SEER database [13]. A persistent rise in NEN incidence has also been confirmed by a retrospective, population-based study in England (1995-2018) [14], while sustained increments in incidence rates were similarly illustrated by epidemiological trends spanning 3 decades in Queensland, Australia [15]. Data from Asia, specifically Japan, contribute to this global picture, documenting thousands of diagnoses of GEP-NENs in a single year [16]. Clinical and pathological data analysis from dedicated cancer registries, such as the Belgian Cancer Registry, provides valuable, localized insights into the variable biological behavior and outcomes of aNENs [17]. A large multi-institutional US study further elucidated the epidemiology of aNENs, concluding they are the third most common NEN location along the digestive tract, and that patients were more likely to be female [18]. Tertiary care studies [19,20] demonstrated that a high prevalence of NETs is found during appendectomy performed for acute appendicitis, emphasizing the frequent incidental nature of the diagnosis, which often lead to unexpected histopathological findings [21]. One retrospective study specifically reported a 2% incidence of NETs in macroscopically normal appendices removed during laparoscopy for acute abdominal pain [22], and the association between aNEN and acute appendicitis has been clearly established [23]. Despite the high frequency of aNENs, data from 1 tertiary center in the Middle East indicated that the pancreas and small intestine were more common sites for GEP-NENs in that specific patient population [24]. Overall, aNENs constitute approximately 31% of all appendiceal tumors identified in 1 national cancer database analysis [25]. The epidemiological risk extends beyond the primary tumor, as population studies in England have reported that patients with NENs have an increased risk of developing second primary malignancies [26]. Finally, the epidemiology of more aggressive variants, such as appendiceal mixed adeno-neuroendocrine carcinoma (MANEC), has been characterized using the SEER registry, emphasizing the need for differentiated pathological and clinical management [27]. A synthesis of the major epidemiological studies describing incidence trends, demographic distribution, and prevalence of incidental aNENs is reported in Table 1.

Table 1 Summary of key epidemiological evidence on aNENs. This table synthesizes major population-based studies, national cancer registries, and large appendectomy series describing incidence trends, prevalence in surgical specimens, demographic patterns, and the global rise in detection of appendiceal neuroendocrine neoplasms. Together, these data confirm aNENs as increasingly common, predominantly incidental findings with overall favorable prognosis and significant geographic variability in reported incidence

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Etiopathogenesis

The complex pathogenesis of appendiceal neoplasms demands precise differentiation among various pathological entities, extending beyond classical NETs to include hybrid and epithelial malignancies. This distinction is important to identify aggressive variants, such as mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), which frequently exhibit unfavorable outcomes and whose specific clinical profile and survival patterns have been established through large genomic analyses utilizing comprehensive registry data [28]. Goblet cell adenocarcinomas, another entity within the range of aggressive appendiceal pathology, demonstrate a specific clinicopathological, immunological and genomic landscape that distinguishes them from classical well-differentiated aNENs [29]. NETs of the small intestine and appendix are known to exhibit extensive chromosomal and methylation alterations [30]. Molecular research has categorized multiple genomic variants using chromosomal copy number variation, specifically the loss of chromosome 18 (18LOH), and have revealed differential methylation patterns in G-protein coupled receptor signaling genes, including the somatostatin gene, which is a crucial target for both clinical imaging and therapeutic intervention [30]. Diagnostic precision and further histological analysis hinge largely upon immunohistochemistry (IHC), which constitutes a system essential for defining the proper oncological architecture [31]. While conventional neuroendocrine antigens, such as chromogranin A and synaptophysin, are still commonly utilized, the nuclear transcription factor INSM1 (insulinoma-associated protein 1) demonstrates superior selectivity regarding neuroendocrine maturation within the digestive system, facilitating exact clinical assessment protocols [32]. Nevertheless, a systematic review comparing IHC biomarkers between appendiceal neuroendocrine and epithelial cell neoplasms has revealed the necessity for future trials to identify the optimal marker combination [31,32]. In addition to the standard neuroendocrine pathways, the molecular profiles of non-neuroendocrine appendiceal lesions, including serrated lesions, polyps and mucinous neoplasms, demonstrate genotypic heterogeneity, emphasizing the complex and divergent carcinogenic pathways active within the appendix [33]. This intricate pathological environment occasionally results in rare appendiceal collision tumors, defined by the coexistence of a neuroendocrine carcinoid and a concomitant mucinous neoplasm, demonstrating the requirement for clinical plans that follow the oncologic rules of each distinct component neoplastic category found therein [34,35]. Given such variety, thorough evaluation of therapeutic strategies is important; for instance, the management of aggressive MiNENs (such as MANEC) has been studied by comparing right hemicolectomy versus appendectomy to clarify the optimal surgical approach and evaluate any survival advantage [36]. Similarly, the appropriate surgical strategy for large appendiceal carcinoids (those exceeding 2 cm) has been assessed using matching score analysis to verify whether right hemicolectomy provides a better survival benefit than simple appendectomy alone [37]. Lastly, new investigations explore novel prognostic markers, including specific microRNAs (miRNAs), such as miR-96 and miR-133a, in GI NENs to possibly help in evaluating the biological behavior and metastatic potential of these complex neoplasms [38].

Clinical presentation

The clinical presentation of aNENs is variable, ranging from specific endocrine syndromes to the frequent scenario of incidental detection [39,40]. Although the majority of aNENs are non-functional, the pathological ranges include rare, but clinically significant, functional syndromes. One such case involved a patient presenting with ectopic Cushing syndrome from an ACTH-secreting appendicular carcinoid, where precise tumor localization was achieved using advanced nuclear medicine techniques such as 68-Ga-DOTATATE PET/CT [41]. Furthermore, exhaustive diagnostic investigation is essential, given the known multifocal behavior of NENs across the GEP tract; aNENs may co-occur with synchronous primary tumors in other GI sites, such as the small intestine, necessitating a full workup to exclude disseminated neuroendocrine disease [42]. The absence of pathognomonic symptoms implies that a high proportion of aNEN cases are discovered during routine histopathological analysis following an appendectomy [39,40]. In fact, the most frequent preoperative clinical manifestation linked to a subsequent eventual aNEN diagnosis is acute appendicitis, which the neoplasm is known to simulate [43,44]. The generic symptoms reported by patients often include abdominal pain, nausea, vomiting and diarrhea [41,42]. This mimicry is occasionally complicated by the presence of a mucocele detectable on CT scan, making the differential diagnosis more difficult [43]. The risk of a missed diagnosis remains high. One report highlighted the diagnostic hazards of conservative management when a NET G1 remained undetected until an interval appendectomy followed non-surgical treatment for acute appendicitis [45]. This phenomenon stems from the tumor’s infiltrative or non-mass-forming growth architecture, which restricts visibility during preoperative radiological imaging [45]. The prevalence of incidental detection, observed across various patients groups, including young patients [40], underscores the importance of mandatory pathological assessment of all appendectomy specimens. Finally, the vague and potentially misleading clinical characteristics of appendiceal NETs, being highly similar to those of acute appendicitis, pose a persistent challenge for diagnosis, particularly in settings where the neoplasm is considered an atypical trigger of appendicitis [46].

Expanding on these incidental observations, a single-center experience over a decade confirmed that NETs represented the most frequently observed incidental findings in appendectomy samples [47]. The clinical manifestation may also involve rare scenarios, such as the disease occurring within an incarcerated Amyand’s hernia; here, an appendiceal carcinoid was identified inside the hernial sac, highlighting the necessity of high suspicion in atypical presentations [48]. Although clinical scores, such as the AIMS65 score (Albumin <3.0 g/dL, International normalized ratio >1.5, Mental status changes, Systolic blood pressure ≤90 mmHg, age ≥65 years) for upper GI bleeding [49], are often employed to evaluate patient prognosis in various conditions, the identification of aNENs depends primarily on pathological review. Nevertheless, the incidental finding of an aNEN, even with a complication such as a perforated appendix, emphasizes the unpredictable nature of its discovery, with 1 case describing a grade 1 appendiceal neuroendocrine tumor (aNET) found incidentally in a young female after emergency surgery for perforated appendicitis [50]. The complex management of these cases requires strict adherence to the oncological principles of the constituent malignancies [34,35]. The necessity for comprehensive workup is further evidenced by instances of synchronous quadruple primary neoplasms, including a collision neoplasm of a NET and a Schwann cell hamartoma in the appendix, along with a colon adenocarcinoma and a sessile serrated adenoma [51].

To underscore this diagnostic difficulty, recent research evidence has confirmed that neuroendocrine malignancies of the appendix often surface unexpectedly, intraoperatively or following surgical resection for presumed inflammation, and represent significant clinical hurdles [52]. This histological range additionally encompasses goblet cell adenocarcinomas, primarily detected among individuals presenting with acute appendicitis symptoms, illustrating the neoplasm’s inherent capacity to mimic benign inflammatory reactive conditions [53].

The likelihood of concurrent lesions remains high, as illustrated by a case involving the rare Leser-Trélat sign—an abrupt onset of multiple seborrheic keratosis—in a patient with synchronous well-differentiated NETs of both the ileum and the appendix [54]. Additionally, the unusual presentation of a NET within an Amyand’s hernia has been confirmed, where the tumor with serosal involvement was found in the appendix during emergency surgery for acute appendicitis in an inguinal hernia [55]. Retrospective studies have highlighted the importance of universal histological examination, revealing that a significant percentage of macroscopically normal appendices removed during laparoscopy for acute right lower quadrant abdominal pain contained a NET [22]. The propensity for these tumors to present as an acute surgical emergency extends to the nearby cecum, where a carcinoid tumor of the cecum presented with the clinical picture of acute appendicitis [56]. Given the diversity in presentation and aggressiveness, comparative analyses are important, showing that the survival profile for typical carcinoids differs significantly from mixed adeno-neuroendocrine carcinomas and adenocarcinomas of the appendix [57]. Finally, the most complex presentations, such as perforated combined mucinous and NETs leading to pseudomyxoma peritonei, necessitate aggressive surgical approaches, including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy [58].

Histology and diagnosis

Establishing a clinical diagnostic pathway for aNENs requires comprehensive histopathological classification and grading [59], employing globally accepted systems from the World Health Organization (WHO) and ENETS guidelines to distinguish between well-differentiated NETs (NET G1-G3) and poorly differentiated NECs, mainly through assessment of the Ki-67 proliferative index and mitotic count [59]. Most cases of aNENs are typically well-differentiated NETs, which usually follow an indolent course when the disease remains localized upon diagnosis [59]; microscopically, aNENs appear morphologically similar to midgut NETs, despite the broad pathological spectrum [9,60]. Well-differentiated NETs of the appendix (A-WDNETs) display diverse tumor growth patterns, including solid, nest, insular, trabecular and acinar formations [61]—a specific single-center study examining these A-WDNETs identified elevated expression levels of the innovative neuroendocrine marker INSM1 throughout those various growth morphologies [61]. Beyond the typical carcinoid form, the pathological spectrum is complicated by other primary appendiceal tumors, such as MANECs and goblet cell carcinomas, which represent highly aggressive, distinct entities requiring tailored classification and management strategies [9,59]. Apart from grading and basic phenotyping, the histopathological report should detail crucial prognostic variables that determine the requirement for extensive surgical resection (right hemicolectomy), including tumor size, depth of invasion (e.g., mesoappendiceal involvement), and the presence of angio- and neuro-invasion [59,61], with the importance of accurate tumor staging (TNM) widely recognized for predicting prognosis, as some studies suggest staging is more reliably associated with adverse clinical outcomes than is grading [59]. Additionally, the condition remains pathologically complex: investigations assessing tumor cellular subtyping imply that, whereas primary small intestinal NETs comprise serotonin-producing EC-cells, the appendiceal variants might contain different cell lineages (e.g., L-cells producing PYY) necessitating further study regarding clinical importance [62]. IHC extends beyond grading: IHC analysis of GEP-NETs has been used in large single-center experiences to investigate the expression of conventional markers, such as synaptophysin and chromogranin A, confirming that most aNENs are typically found incidentally at the tip and exhibit an indolent nature [63]. Research into targeted next-generation sequencing of well-differentiated appendiceal NETs is currently ongoing to discover particular molecular hallmarks, thereby enhancing the underlying genetic knowledge of these specific malignancies [64]. Monitoring the expression of individual transcription factors remains key for assigning the primary site of origin in NETs; strong expression of SATB2 (special AT-rich sequence-binding protein 2) occurs only in well-differentiated tumors arising from the lower GI tract (including the appendix and rectosigmoid), providing a diagnostic tool to distinguish them from tumors of foregut or midgut origin [65]. IHC challenges persist in mixed tumors, where INSM1 demonstrates positivity in a significant portion of the aggressive adenocarcinoma ex-goblet cell carcinoids, even though the majority of tumor cells lack staining for conventional neuroendocrine markers [66]. Chemokine receptor 4 (CXCR4) in GI NENs constitutes the focus of retrospective study, with IHC analysis aiming to characterize its prognostic presence in these tumors [67]. Finally, emerging research is focusing on molecular biomarkers such as miRNAs, with studies aiming to evaluate their use as adjunct tissue markers for classifying and grading well-differentiated GEP-NETs, potentially providing additional tools for assessing the biological behavior of aNENs [68].

Undoubtedly, the primary challenge in the diagnostic pathway of appendiceal neoplasms is achieving accurate preoperative localization and characterization, often within the context of acute abdominal pain, and the overall diagnostic process must recognize the pathological heterogeneity of appendiceal tumors, which constitute a wide spectrum of diseases encompassing typical NETs (TNETs), goblet cell carcinoids and signet-ring cell tumors, all exhibiting different patterns of presentation and, crucially, distinct outcomes [69]. Ultrasound (US) is a primary noninvasive imaging tool utilized for evaluating children presenting with acute right iliac fossa pain and suspected appendicitis; a specific study evaluated the diagnostic accuracy of US in this pediatric population, highlighting its role in the differential diagnosis [70]. This precise histopathological differentiation is crucial, as the final diagnostic classification directly guides the major therapeutic decisions [71]. The diagnostic workup must account for rare functional syndromes, such as ectopic Cushing syndrome, where precise localization is crucial and can be achieved using advanced nuclear medicine techniques such as 68-Ga-DOTATATE PET/CT [39]. Given that aNENs are often incidentally discovered during appendectomy [6], postoperative management hinges on risk stratification, particularly regarding the need for complementary right hemicolectomy (RHC) [71]. For incidental tumors less than 20 mm in diameter located at the appendiceal base, the absence of poor prognostic factors at histopathological examination remains an important indication of whether a simple appendectomy is sufficient [72]. Deciding whether a patient needs regional lymphadenectomy depends on the risk of nodal metastasis, which current guidelines often base solely on tumor size; however, a more accurate predictive tool is offered by a newer model combining depth of invasion and tumor size [73], underscoring the critical role of pathological factors beyond size alone, while the core debate over RHC versus simple appendectomy for tumors sized between 1-2 cm remains central [71]. IHC plays a useful role in diagnosis and molecular classification, with the expression of specific markers, such as PCSK2 (prohormone convertase 2), having been evaluated for its utility in a panel approach to distinguish between foregut and midgut NETs [74]. Furthermore, specific transcription factor IHC, such as SATB2, has been shown to distinguish Islet1 positive rectal NETs from pancreaticoduodenal NETs, a principle that aids in establishing the lower GI tract origin of appendiceal NETs [75]. However, the role of advanced imaging post-resection is limited; retrospective analyses have shown that routine early postoperative 68-Ga-DOTATATE PET/CT has a low yield in incidental appendiceal NETs [76]. The determination of whether to perform oncological completion surgery remains a critical challenge, with studies evaluating the reliability of proposed risk criteria by comparing histopathological findings with disease-free survival [77]. The clinical utility of SATB2 has been verified in an extensive tissue microarray study analyzing thousands of tumors [78]. The foundation of the workup is the pathological report, which classifies aNETs—the most common neoplasm of the appendix—and provides the critical size, LVI, and pT category data [79]. The necessity for careful pathological review is further highlighted by the complexity of rare entities, such as appendiceal collision tumors, which require adherence to the oncological principles of the component tumor types (neuroendocrine and mucinous neoplasms) [35]. The principal histopathological patterns, diagnostic markers, and prognostic features of aNENs are outlined in Table 2.

Table 2 Key histopathological features, diagnostic markers, and prognostic criteria of aNENs. This table summarizes the main histological patterns, diagnostic markers, molecular features, and prognostic factors that guide the classification and management of aNENs

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Outcome

aNENs generally have a favorable prognosis; however, their outcomes depend on accurate risk stratification and appropriate surgical planning, with the central debate concerning the necessity of colon resection (RHC) [80]. A systematic review and meta-analysis focusing on the histopathological diagnosis of aNENs evaluated the specific criteria that should mandate an RHC [81]. The established risk factors for nodal metastasis (N+) that require RHC include tumor size, histological grade and LVI, particularly when the tumor size exceeds 2 cm, or if LVI is present [59,81]. Since LVI is often difficult to detect and is associated with a worse prognosis, its presence is a significant marker; studies have shown that LVI is highly associated with lymph node involvement, even in small appendiceal NETs 1-2 cm, regardless of histology (typical, goblet cell, or composite) [82]. The surgical management of tumors within the disputed 1-2-cm diameter range has been thoroughly investigated: a large database analysis compared the clinical outcomes of simple appendectomy to RHC in this cohort, and concluded that RHC generally does not confer a significant survival advantage for most 1-2 cm tumors, suggesting that appendectomy may be sufficient in the absence of other high-risk factors [83]. In contrast, a comparative study, assessing whether colon resection truly enhances outcomes across a diverse patient population, found that simple appendectomy with negative resection margins was associated with overall survival (OS) comparable to RHC [80]. However, the pathological assessment remains vital, as prognostic features such as tumor size, depth of invasion (e.g., mesoappendiceal invasion), and angio- and neuro-invasion are essential for identifying the minority of patients who truly require an RHC [59,80]. The prognostic factors that guide surgical decision-making encompass various microscopic features [84]. Specifically, regarding well-differentiated neuroendocrine (carcinoid) tumors of the appendix, the clinical importance of small vessel invasion in addition to size has been shown to be a useful feature associated with metastatic disease [84]. Further stratification is necessary for very small tumors, as low-stage tumors smaller than 5 mm appear to be overwhelmingly indolent and may merit a separate designation, challenging the conventional cutoffs for risk assessment [85]. A 10-year audit of clinical characteristics and results confirmed that, while appendectomy is mostly curative in the majority of cases, guidelines recommend RHC for those with specific high-risk features, despite the absence of definitive data supporting a survival benefit from the RHC itself [86]. When analyzing the management of 1-2-cm carcinoid tumors specifically using the National Cancer Data Base (NCDB), a retrospective cohort study found that RHC failed to provide a statistically significant OS advantage compared to primary resection alone [87]. Lymph node status remains the primary predictor of disease recurrence, making the adequate surgical sampling of lymph nodes crucial [88]. A study analyzing the role and prognostic significance of mesenteric lymphadenectomy in well-differentiated aNENs identified the risk of lymph node metastases as a function of tumor size, supporting the practice of nodal evaluation in higher-risk patients [88]. Lastly, a large retrospective, Europe-wide, pooled cohort study focusing on the surgical management of aNETs sized 1-2 cm reinforced this conservative approach, concluding that RHC is limited primarily to cases with incomplete tumor resection or high-grade G2 or G3 aNENs [89]. The controversy regarding the surgical relevance of lymph node involvement and RHC on OS in aNENs remains central [90]. A comparative analysis of primary NETs and non-NET appendiceal cancers in the US found that NENs occurred at a younger age, and were less prone to present with metastatic disease, yet for both groups surgical resection was the cornerstone of treatment [91]. This same study showed that non-NET appendiceal cancers (such as adenocarcinoma) were often treated similarly to colon cancers, while NETs had a higher OS [91]. Retrospective cohort studies characterizing the trends in RHC utilization found that the rate of RHC for NEN decreased over time, while RHC failed to demonstrate a significant OS benefit for localized NENs [25]. A comprehensive characterization of aNEN patients referred to a European NET Center of Excellence confirmed that tumor size and Ki-67 index were strongly associated with adverse outcomes, guiding their surgical approach [92]. Further studies evaluating the necessity of RHC in high-risk aNENs determined that, while guidelines suggest RHC for high-risk features, its association with disease-free survival is not always conclusive [93]. Negative factors that negatively affect survival outcomes include tumor grade, age, and extent of disease, with Black patients in 1 study showing a statistically significant higher rate of advanced disease at presentation [94]. Metastatic spread to sites such as the liver has also been reported [94]. The overall treatment and follow-up algorithms for aNENs continue to change in light of new guidelines and our evolving understanding of disease progression [95]. This retrospective analysis confirms that ANETs are the most common appendiceal tumors, often detected incidentally during emergency appendectomy, underscoring the challenge in preoperative diagnosis and the continuous evolution in management strategies [95]. The necessity for comparing surgical options is further emphasized in aggressive variants, where the management of appendiceal MiNENs involves an ongoing comparison of RHC versus appendectomy to determine whether RHC confers a significant survival advantage for this aggressive entity [36]. Finally, the treatment of appendiceal tumors that result in peritoneal surface malignancies requires specialized care; while the difficulties in deciding upon cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases are known, it remains an established treatment for peritoneal metastases arising from appendiceal tumors [96].

Surgical risk stratification is summarized in Fig. 2, while Table 3 summarizes the key management recommendations for aNENs across major international guidelines, highlighting areas of consensus and the persisting controversy in the 1-2 cm subgroup.

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Figure 2 Surgical management of appandiceal neuroendocrine tumors: appendectomy vs. right hemicolectomy.

Summary of current criteria guiding the choice between appendectomy and RHC in aNETs. Appendectomy is appropriate for tumors <1 cm and for 1-2 cm lesions lacking high-risk features (lymphovascular or perineural invasion, deep mesoappendiceal invasion, positive margin, or intraoperative nodal disease). RHC is recommended for tumors >2 cm and for 1-2 cm tumors with any adverse feature, as well as for poorly differentiated NEC/MiNEN. Management in pediatric and pregnant patients generally favors appendectomy, with RHC often deferred in pregnancy

aNET/aNETs, appendiceal neuroendocrine tumor/tumors; RHC, right hemicolectomy; R0, microscopically margin-negative resection; R1, microscopically margin-positive resection; LVI, lymphovascular invasion; PNI, perineural invasion; NEC, neuroendocrine carcinoma; MiNEN, mixed neuroendocrine–non-neuroendocrine neoplasm; ENETS, European Neuroendocrine Tumor Society; G1, grade 1; cm, centimeters; mm, millimeters; vs, versus

Table 3 Management recommendations for aNENs across major international guidelines. This table compares the main surgical and management recommendations for aNENs provided by ENETS, NANETS, ESMO and AIOM, highlighting areas of consensus and the key differences in the 1-2 cm tumor subgroup

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Special populations

NENs in children and adolescents represent an exceedingly rare population, with an estimated prevalence of approximately 2.8 cases per million [97]. In this rare population, among all GEP-NENs, the appendix remains the most frequent primary site, with diagnoses often occurring incidentally after appendectomy for suspected appendicitis [97].

Pediatrics

Pediatric aNETs typically exhibit a positive clinical prognosis, and are usually small (median size 0.9 cm [98] or 8 mm [99]). Such good characteristics have been widely confirmed: both the German MET registry (662 cases) and the Danish national cohort (205 cases) reported no tumor-related mortality or recurrence [100,99]. The management of aNETs in children remains controversial, as guidelines have historically been extrapolated from adult data, which recommend aggressive procedures, such as completion RHC, for tumors above certain size thresholds or with high-risk features [97]. However, extensive pediatric data strongly argue against this approach. Even in the presence of lymphovascular spread, lymph node metastases, or tumor size ≥1.5 cm, the prognosis remains excellent, with risk factors showing no impact on outcome [100]. Accordingly, additional surgical procedures offer no therapeutic advantage, according to consistent reports from multiple single-center experiences and cohorts [101]. This consensus supports the position that appendectomy alone is sufficient and curative for most pediatric aNETs [98,101]. The presence of multifocal aNETs (2-5 tumors) is also rare, but a case series suggests this pattern does not predict local advanced or metastatic disease and, therefore, does not warrant more aggressive treatment [102]. Occurrence of aNETs alongside genetic conditions, such as a de novo MLH1 gene pathogenic variant causing Lynch Syndrome (LS) [103], or with parasitic bowel infections such as Enterobius vermicularis [104], has been reported, raising the intriguing, though unproven, hypothesis of inflammation-related carcinogenesis [104]. Nevertheless, the appendiceal NEN associated with LS was found to exhibit proficient mismatch repair expression, indicating the tumor was not related to the germline MLH1 deletion [103]. Additional diagnostic challenge arises when aNETs coexist with other rare abdominal pathologies, such as intestinal malrotation and Fitz-Hugh-Curtis syndrome, complicating the differential diagnosis of chronic intermittent abdominal pain [98]. NENs originating outside the appendix and pancreas are significantly rarer. Well-differentiated NENs from other GI sites (e.g., stomach and colorectum) present in 31.3% of cases with distant metastases, a high rate for pediatrics, but lower than in adults [101]. Nevertheless, these patients demonstrate a favorable prognosis (3-year OS of 93.3%) following treatment involving comprehensive operative excision [105]. Conversely, poorly differentiated GEP-NECs are highly aggressive, with the 5-year OS being 85.4% [106]. The principal prognostic indicator is the original site, since pancreatic GEP-NECs yield the lowest longevity (56.0% after 5 years), whereas non-metastatic illness across all regions displays a superior clinical survival rate (97.7%) relative to juvenile patients suffering from metastatic overall disease (52.7%) [106]. The rarity and biological aggressiveness of GEP-NECs require individualized management within a dedicated multidisciplinary team [106]. Finally, distant metastatic dissemination—particularly to the liver—has been reported even among younger patients, underscoring the need for early recognition and optimized therapeutic strategies [103].

Pregnancy

Regarding aNENs in women, diagnosis during pregnancy is extremely rare, occurring most commonly within the third trimester [107,99]. Evaluation of cases diagnosed during gestation found favorable pregnancy outcomes and excellent long-term prognosis, suggesting that a conservative management approach may be considered, with RHC often postponed to the postpartum period [107]. The rarity of appendiceal NETs can lead to challenging or delayed diagnosis, as symptoms may be nonspecific, mimicking conditions such as appendicitis or pyelonephritis [108].

Concluding remarks

The future management of aNETs is rapidly evolving towards a precision model that incorporates advanced technological and biological insights. Artificial intelligence (AI) is set to become a useful tool, particularly in radiomics and digital pathology, important for improving risk stratification and refining surgical planning, and useful for guiding the choice between appendectomy and RHC [109]. At the same time, significant therapeutic progress has been focused on optimizing peptide receptor radionuclide therapy (PRRT), through combination studies involving radiosensitizers, or the exploration of next-generation alpha emitters, which promises to expand PRRT’s efficacy even to higher-grade NETs [110]. A key emerging research frontier is the host-tumor metabolic interaction. In particular, prospective multicenter analyses are critically needed to systematically study the “obesity paradox”—where a higher body mass index correlates with better outcomes in certain GI malignancies—to determine its relevance and underlying mechanisms in aNETs [111]. Clarifying whether chronic inflammation or altered adipokine profiles influence the tumor microenvironment might redefine risk assessment, and potentially introduce metabolic modulation or lifestyle modification as an adjuvant therapeutic strategy [112].

In conclusion, the ultimate goal is to shift the management paradigm entirely from size-based algorithms to robust predictive models shaped by the integration of molecular, imaging (AI), and personalized patient metabolic data, ensuring optimal oncological safety balanced with therapeutic restraint.

Acknowledgments

The authors would like to acknowledge the Departments and Sections involved in this work at Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, including the Sections of Endocrinology, Medical Oncology, Anatomic Pathology, Diagnostic Imaging, Nuclear Medicine, and Digestive Surgery, for providing an inspiring clinical and academic environment throughout the development of this narrative review.

The authors further clarify that no individuals other than those listed as authors contributed significantly to the manuscript.

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Notes

Conflict of Interest: None