Neuroendocrine tumors of the appendix: a comprehensive review of the literature and case presentation.

A 42-year-old male with no notable past medical history presented with acute onset right lower quadrant abdominal pain of less than 72 hours’ duration, in the absence of additional GI or systemic symptoms. On physical examination, he was hemodynamically stable, afebrile (37°C), and showed no signs of respiratory distress. Abdominal evaluation revealed localized tenderness with positive Rovsing’s and Blumberg’s signs, but no palpable masses. Laboratory investigations demonstrated a white blood cell count of 10.1×103/μL with neutrophilia (77.2%), hemoglobin of 16.2 g/dL, platelet count of 198×103/μL, elevated C-reactive protein (CRP) at 33 mg/L, normal serum sodium (140 mmol/L), and creatinine level of 1.09 mg/dL; coagulation parameters were within normal limits. Digital rectal examination was unremarkable. Imaging studies, including abdominal ultrasonography (Figure 1 ) and MRI (Figure 2A , 2B ), revealed findings consistent with acute appendicitis. The patient underwent a laparoscopic appendectomy (Figure 3 ), during which the appendix was found to be 5 cm in length with a thickened wall and a distal tip measuring over 1 cm, exhibiting a pale, nodular, tumor-like appearance. The surgical resection was completed without intraoperative complications. Postoperatively, the patient received a full course of antibiotics and was discharged in stable condition on postoperative day two, with an uneventful recovery. Abdominal ultrasound demonstrating signs of appendiceal inflammation (A and B) The magnetic resonance imaging (MRI) revealed features consistent with inflammation of the appendix suggestive of acute appendicitis The intraoperative laparoscopic assessment revealed an appendix with a markedly thickened wall and distal distension exceeding 1 cm, exhibiting a pale, nodular appearance suggestive of a tumor-like lesion HP examination of the resected specimen revealed features consistent with acute appendicitis, along with a well-differentiated (G1) NE tumor of the appendix (carcinoid type). The appendiceal tumor was composed of cells organized into nests or islands, separated by fine septa of collagen fibers. In the tumor area, the wall of the appendix was thickened, rich in collagen fibers (Figure 4 ). The tumor exhibited intraluminal proliferation with focal extension into the adjacent adipose tissue, and mitotic activity was low, with fewer than 2 mitoses per 10 high-power fields (HPFs). Microscopic image of the appendix. Its lumen is occupied by round tumor cells, organized in islets, separated by thin conjunctive septa. Hematoxylin–Eosin (HE) staining, ×200 The study of the tumor cells with powerful microscopic objectives showed that the tumor was composed of two different types of cells: some larger, with abundant, vacuolar, weakly acidophilic cytoplasm and other smaller cells, with less and intensely acidophilic cytoplasm (Figure 5 ). The tumor islets contained two different cell types: some larger cells with abundant, vacuolar, weakly acidophilic cytoplasm and other smaller cells with less cytoplasm and intensely acidophilic cytoplasm. HE staining, ×400 For a more accurate HP diagnosis, we performed several IHC reactions using the antibodies: anti-CgA (monoclonal mouse anti-human CgA, clone DAK-A3, 1/100 dilution, Dako); anti-SYN (monoclonal mouse anti-SYN, clone SY38, 1/50 dilution, Dako); anti-aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) (clone PA5-32127, 1/500 dilution, Invitrogen); anti-CD56 (monoclonal mouse anti-human CD56, clone 123C3, 1/100 dilution, Dako); anti-caudal type homeobox 2 (CDX2) (monoclonal mouse anti-CDX2, clone DAK-CDX2, 1/100 dilution, Dako); anti-cytokeratin (CK) AE1/AE3 (monoclonal mouse anti-human CK, clone AE1/AE3, 1/100 dilution, Dako). IHC staining demonstrated strong positivity for CgA, SYN, ALDH1A1, CD56, and CDX2, supporting the NE origin of the lesion (Figure 6A , 6B , 6C , 6D ). Intense reaction of tumor cells to anti-CgA (A), anti-SYN (B), anti-ALDH1A1 (C), and anti-CD56 (D) antibodies. Immunolabeling with anti-CgA antibody: (A) ×200. Immunolabeling with anti-SYN antibody: (B) ×200. Immunolabeling with anti-ALDH1A1 antibody: (C) ×200. Immunolabeling with anti-CD56 antibody: (D) ×200. ALDH1A1: Aldehyde dehydrogenase 1 family, member A1; CD56: Cluster of differentiation 56; CgA: Chromogranin A; SYN: Synaptophysin In contrast, the use of anti-CK AE1/AE3 antibody showed that there are two phenotypes of tumor cells: some intensely positive to anti-CK AE1/AE3 antibody immunolabeling, others negative (Figure 7 ). Intense positive or negative tumor cells to anti-CK AE1/AE3 antibody. Immunolabeling with anti-CK AE1/AE3 antibody, ×200. CK: Cytokeratin The detection of an appendiceal tumor, and especially the diagnostic uncertainty, generates depression and anxiety. Depression emphasizes proinflammatory activity both in the brain and in the periphery. In the brain, increased inflammatory activity can cause activation of the hypothalamic–pituitary–adrenal (HPA) axis, with massive release of endogenous cortisol with a significant decrease in endogenous neuroprotective factors [brain-derived neurotrophic factor (BDNF)]. During this cycle, glutamate is excessively released, causing excitotoxicity in the hippocampus and frontal cortex. These mechanisms can produce neuronal apoptosis with hippocampal and frontal cortex atrophy disturbing the cognitive circuit. The persistence of proinflammatory markers [CRP and interleukin-6 (IL-6)] may indicate to the clinician the presence of depression and therapeutic resistance [ 52 ] but also the risk of autolytic behaviors [53 53 ] especially in young patients operated for appendiceal tumor, while for older patients in the same cynical situation, it indicates a potential risk of triggering the neurodegenerative mechanisms of Alzheimer’s disease [ 54 4]. In this context, an operated appendiceal tumor requires monitoring in a multidisciplinary therapeutic team.

aNETs are most often discovered incidentally, with no clearly defined risk factors for their development. However, young age, female sex, and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) may be associated with increased risk. Pathological features like tumor size >2 cm, mesoappendiceal invasion, positive resection margins, and a high Ki67 index are linked to more aggressive behavior and metastatic potential. Additionally, tumor location at the base of the appendix and the presence of lymphovascular invasion can negatively impact prognosis and require individualized therapeutic assessment [ 37 ]. Ghattas et al. (2023) reports a rare familial case of aNET, underscoring the importance of considering genetic predisposition and family history in management and screening, despite such occurrences being exceptionally uncommon [ 40 ].

Appendiceal neuroendocrine tumors (aNETs) represent a subset of neoplasms that can manifest with a range of clinical presentations [ 1 ]. With the growing availability and utilization of advanced diagnostic technologies, the frequency of incidentally discovered aNETs has been steadily increasing. Despite this trend, the term ‘incidental aNET’ remains ambiguously defined in the current literature [ 2 ]. A practical definition may encompass tumors identified during histopathological (HP) evaluation following appendectomy for suspected acute appendicitis, or lesions detected through imaging performed for unrelated clinical indications in asymptomatic patients [ 3 ]. This case underscores the importance of integrating medical education with clinical vigilance, highlighting that even experienced clinicians may inadvertently overlook such lesions without a high index of suspicion.

Benign appendiceal tumors are rare and include carcinoid tumors, the most common subtype, typically located in the distal third of the appendix and characterized by indolent behavior with a low metastatic risk if smaller than 1 cm. Appendiceal mucocele, caused by luminal obstruction from benign lesions such as mucinous cystadenoma or retention cysts, may progress to PMP if ruptured. Other rare benign tumors include lipomas and stromal tumors (such as low-risk GISTs), which require surgical excision only if symptomatic or large, with histological confirmation needed in the latter. Additionally, adenomatous polyps and appendiceal endometriomas may occasionally be found, particularly in the setting of pelvic endometriosis [ 14 , 15 ].

The positive diagnosis of aNETs is often incidental, typically identified following an appendectomy performed for acute appendicitis, with confirmation through HP examination showing monomorphic cells with “salt-and-pepper” chromatin arranged in trabecular, insular, or acinar patterns, accompanied by fibrovascular stroma. Immuno-histochemistry supports the diagnosis by demonstrating positivity for NE markers such as chromogranin A (CgA), synaptophysin (SYN), and cluster of differentiation 56 (CD56), with Ki67 indexing essential for tumor grading (G1–G3). In cases involving tumors ≥2 cm or suspected disease spread, advanced imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), or Dotatate positron emission tomography (PET)–CT, are recommended to assess loco-regional or metastatic involvement [ 37 ]. The differential diagnosis of aNETs includes other neoplastic entities such as appendiceal adenocarcinoma, mucinous tumors (e.g., LAMN, HAMN), MiNENs, poorly differentiated NECs, and metastatic lesions from extra-appendiceal primaries, each with distinct histological and immunohistochemical (IHC) profiles. Inflammatory and reactive conditions like chronic or granulomatous appendicitis, NE cell hyperplasia, and appendiceal endometriosis may also mimic tumor pathology but lack cytological atypia and show specific immunoreactivity patterns. Accurate distinction requires comprehensive HP and IHC evaluation to guide appropriate management [ 28 ]. Establishing the differential diagnosis between aNETs and right-sided colonic ischemia is of particular importance, as both conditions can present with overlapping clinical symptoms, such as right lower quadrant abdominal pain, and may be easily misinterpreted in the absence of thorough imaging and HP evaluation [ 38 ]. The differential diagnosis between aNETs and ovarian pelvic masses is essential, given the possibility that an ovarian lesion may represent either a primary tumor or a metastasis of appendiceal origin, necessitating thorough imaging and HP evaluation to accurately determine the tumor’s origin [ 39 ].

Appendiceal tumors are rare neoplastic entities, accounting for less than 2% of all gastrointestinal (GI) tract malignancies, with malignant forms, particularly adenocarcinomas, being incidentally identified in approx. 0.2–1.5% of appendectomy specimens and representing 20–26% of all appendiceal neoplasms [ 1 ]. Carcinoid tumors, making up around 80% of appendiceal neoplasms, are typically small and metastasize to the peritoneum rather than the liver, while mucinous neoplasms, though often indolent, can cause severe outcomes if disseminated; laparoscopic surgery is increasingly preferred for their management [ 2 , 3 ]. Multiple factors may elevate the risk of developing appendiceal cancer, including advancing age – most commonly between 40 and 60 years, and a higher incidence of aNETs among females. Tobacco use is a recognized risk factor for various malignancies, including those of the appendix. Certain underlying medical conditions, such as atrophic gastritis, pernicious anemia, and Zollinger–Ellison syndrome, as well as a potential hereditary predisposition, may also contribute, though additional studies are needed to confirm a genetic link [ 4 ]. The pathogenesis of appendiceal malignancies remains poorly defined, though it is hypothesized that appendiceal mucinous neoplasms (AMNs) may progress via a colorectal-like adenoma–carcinoma sequence involving early Kirsten rat sarcoma viral proto-oncogene (KRAS) mutations, followed by alterations in tumor protein p53 (TP53), adenomatous polyposis coli (APC), and β-catenin (CTNNB1) genes, with an alternative mechanism implicating microsatellite instability due to defects in mismatch repair genes such as human MutS homolog 2 (hMSH2), human MutL homolog 1 (hMLH1), PMS1 homolog 1, mismatch repair system component (PMS1), PMS1 homolog 2, mismatch repair system component (PMS2), and MutS homolog 6 (MSH6, GTBP) [ 5 , 6 , 7 ]. Appendiceal neoplasms are infrequent entities, comprising a diverse spectrum of both benign and malignant pathologies. Although their overall incidence is low – ranging from 0.03% to 0.4% – they represent the most prevalent type of neoplasm arising in the vermiform appendix within the spectrum of GI tumors [ 8 ].

Adenomas and sessile serrated lesions (SSLs) of the appendix are exceedingly rare, predominantly incidental HP findings, with retrospective analyses identifying such lesions in only a small fraction of over 3500 appendectomy specimens. Characterized by a distinctive saw-tooth glandular architecture, SSLs are typically non-dysplastic, though cases of low- and high-grade dysplasia have been documented; larger lesions may cause appendiceal obstruction and subsequent inflammation, and those located near the appendiceal orifice may be detectable via colonoscopy [ 16 , 17 , 18 ]. In cases of appendiceal adenomas, as with colorectal counterparts, the feasibility of endoscopic ablation should be assessed, with endoscopic full-thickness resection showing a high R0 resection rate (93%) but a notable risk of post-procedural appendicitis (17%); when endoscopic removal is not viable, minimally invasive appendectomy – potentially including cecal pole resection – should be performed, followed by no further treatment if resection is complete, and surveillance should adhere to the National Disease Management (S3) Guideline for Colorectal Cancer [ 19 ]. This category encompasses LAMN and HAMN, defined by dysplastic, mucin-producing epithelium, extracellular mucin accumulation, and a non-invasive, pushing growth pattern; upon perforation, mucin may disseminate into the peritoneum, termed peritoneal mucinosis, if acellular, or PMP, if associated with neoplastic epithelial cells. LAMNs, typically affecting women in the 5th to 7th decades and classified as grade 1 tumors [ 8 ], are non-invasive lesions marked by low-grade atypia and appendiceal distension; while appendectomy is curative in non-perforated, localized cases, extensive peritoneal spread requires cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) [ 20 ]. Cytoreductive surgery combined with HIPEC is intended to remove both visible tumor burden and residual microscopic disease, with patient outcomes strongly influenced by the presence or absence of tumor cells within peritoneal mucin – acellular mucinosis correlates with improved progression-free survival compared to cellular forms seen in PMP [ 13 ]. Systemic chemotherapy has not demonstrated efficacy in improving survival for LAMN, and current surveillance protocols recommend imaging and tumor marker monitoring every six months for five years to ensure early detection of recurrence [ 21 , 22 ]. HAMNs, classified as grade 2 tumors by the WHO, exhibit focal high-grade dysplasia and are more often linked to high-grade PMP, indicating a poorer prognosis. Peritoneal Surface Oncology Group International (PSOGI) Guidelines recommend appendectomy for non-perforated cases without radiological signs of spread, while perforated or disseminated cases require the right hemicolectomy and cytoreductive surgery with HIPEC, though evidence is limited due to the rarity of these tumors [ 8 ]. Appendiceal adenocarcinomas are invasive malignant glandular tumors classified into non-mucinous, mucinous, signet ring cell, and undifferentiated subtypes, with grading based on histological features – mucinous and signet ring cell carcinomas require >50% mucin or signet cells, respectively, while undifferentiated tumors lack definitive histological or molecular characteristics aside from epithelial marker expression [ 8 ]. In cases of incidentally identified appendiceal adenocarcinoma, appendectomy is considered sufficient for completely excised pTis and low-risk pT1 tumors, while the presence of high-risk features – such as poor differentiation (G3), angioinvasion, or positive surgical margins – as well as tumors classified ≥pT2, necessitates oncological right hemicolectomy with regional lymph-adenectomy; current evidence on adjuvant chemotherapy remains inconclusive, and PSOGI Guidelines provide only a discretionary recommendation following cytoreductive surgery [ 21 , 23 ]. Research on palliative chemotherapy for appendiceal adenocarcinomas is sparse, and in the absence of complete cytoreduction, standardized therapeutic guidelines are lacking. Treatment approaches typically follow protocols established for CRC, particularly for poorly differentiated or advanced-stage tumors, with systemic therapy decisions guided by lymph node status, prognostic factors, and molecular markers, although the efficacy of targeted agents like anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) therapies remain unproven in this setting [ 24 , 25 ]. Goblet cell adenocarcinoma, recognized as a distinct entity in the 2019 WHO Classification, is a rare appendiceal neoplasm characterized by mixed goblet cell, endocrine, and Paneth-like differentiation, classified into three grades based on the proportion of low- to high-grade architecture, and represents 10–23% of primary appendiceal tumors, typically diagnosed in the sixth decade with no sex predilection [ 8 , 26 , 27 ]. aNETs, with a low incidence of 0.12 per million annually, originate from neural crest-derived enterochromaffin-like cells and are typically well-differentiated, in contrast to the more aggressive, poorly differentiated NECs and the rare mixed neuroendocrine (NE)–non-NE neoplasms (MiNENs); often mimicking acute appendicitis, these tumors are frequently diagnosed incidentally, with NETs following distinct grading and staging criteria, unlike NECs and MiNENs, which exhibit more aggressive behavior [ 28 ]. Their incidence varies geographically: rectal NETs predominate in the U.S., jejunal/ileal NETs in Asia, while in Italy, aNETs occur at rates comparable to small intestinal NETs in Asia [ 29 ]. According to the 2019 WHO framework, aNETs are classified by histological grade and differentiation, using mitotic count and Ki67 index as key criteria (Table 1 ): 1. Well-differentiated NETs, graded based on mitotic count and Ki67 proliferation index; 2. Poorly differentiated NECs, high-grade tumors with poor differentiation and aggressive behavior: ▪ Small cell NEC; ▪ Large cell NEC. 3. Mixed MiNENs: ▪ Tumors containing both NE and non-NE components (e.g., adenocarcinoma); ▪ Each component must represent at least 30% of the tumor [ 15 ]. Classification of appendiceal NETs according to the 2019 WHO framework Grade Mitotic count (per 10 HPFs) Ki67 index [%] Characteristics NET G1 20 >20% High-grade, well-differentiated but biologically aggressive NEC (G3) >20 >20% Poorly differentiated HPF: High-power field; NEC: Neuroendocrine carcinoma; NET: Neuro-endocrine tumor; WHO: World Health Organization The 2022 WHO Classification refines the histological grading of aNETs, defining three categories based on mitotic count and Ki67 index. G1 NETs require a tumor size ≥0.5 cm, Ki67 index <2%, and characteristic morphology including nested or trabecular architecture within fibrovascular stroma, with low nuclear density and moderate cytoplasm. Slight variations in cytological features or Ki67 indices up to 5% may still fall within the G1 category in extrapulmonary NETs. According to the WHO 2022 Guidelines, G2 extrapulmonary NETs are defined by NE marker positivity, nested or trabecular architecture, minimal necrosis, and a Ki67 index between 3% and 20%. G3 NETs are characterized by infiltrative, non-encapsulated growth, frequent necrosis, and a high Ki67 index, though classification may be nuanced when architectural features are limited; in such cases, G3 designation is primarily used to guide therapeutic decisions [ 30 ]. Alkhayyat et al. (2021) identify the appendix as the third most common site for GI NETs in the U.S., with aNETs representing approx. 0.3–0.7% of gastroenteropancreatic (GEP)-NETs and 5–25% of appendiceal tumors. These tumors have an annual incidence of 0.1–0.5 per 100 000, occur predominantly in women (65–70%), and are typically diagnosed between ages 40 and 52. Most arise in the distal third of the appendix, are well-differentiated, subserosal or intramuscular, <1 cm in size, asymptomatic, and may occasionally be associated with non-functioning carcinoid syndrome [ 30 ]. aNETs constitute approximately 11% of GEP-NETs, with a population prevalence of 0.38%, typically presenting as small, polypoid, and indolent lesions unless advanced. A national epidemiological study in the U.S. reported an 87% increase in incidence from 2014 to 2019, reaching 2.4 cases per million in 2019. Despite their rarity – found in only 0.07% of appendectomy specimens – aNETs are the most common malignancy of the appendix and the third most frequent GI NET, with Hispanic individuals exhibiting a nearly twofold increased risk compared to Caucasians [ 31 . aNETs primarily affect young males, often presenting in the second to third decades of life, with lesions <2 cm typically well-differentiated and associated with low metastatic potential. While tumors <2 cm are usually managed with appendectomy and surveillance, those ≥2 cm warrant right hemicolectomy due to increased aggressiveness; however, factors such as invasive features, grade ≥2, or nodal involvement may justify more extensive management even in smaller tumors. The absence of standardized guidelines has led to variability in treatment approaches and clinical decision-making [ 32 ]. MiNENs are defined by the presence of both NE and non-NE components, each constituting over 30% of the tumor, with the non-NE component most commonly being adenocarcinoma. MiNENs represent a distinct and rare tumor subtype, requiring precise histological differentiation for accurate classification [ 33 , 34 ]. The non-NE component of MiNENs, typically adenocarcinoma but occasionally other epithelial types, holds clinical significance in differentiating these tumors from composite, collision, and amphicrine neoplasms. MiNENs arise from a common progenitor cell, unlike collision tumors, underscoring their distinct histogenesis and highlighting their unique classification within mixed NE neoplasms [ 35 ]. Zheng et al. (2020) analyzed 315 cases of appendiceal MiNENs – rare biphasic tumors with ≥30% NE and non-NE components – and found an increase in incidence from 0.01 to 0.07 per 100 000. Most cases involved large, high-grade tumors diagnosed at advanced stages, with 5-year overall survival (OS) at 57.4%. Tumor extension, rather than size, grade, or surgical extent, was the only independent prognostic factor influencing survival, with outcomes worse than for NETs or mucinous adenocarcinomas, but better than for non-mucinous or signet ring carcinomas [ 36 ]. The study concludes that appendiceal MiNENs are biologically aggressive neoplasms associated with poor prognostic outcomes, highlighting the critical role of early diagnosis and accurate staging. Findings suggest that more extensive surgical interventions do not necessarily confer a survival advantage, thereby supporting the need for individualized, risk-adapted therapeutic approaches.

Treatment of aNETs is guided by tumor size, location, grade, and adverse histological features: lesions 2 cm or with high-risk features typically warrant right hemicolectomy due to increased metastatic potential. In cases of metastatic or unresectable disease, options for systemic treatments may include somatostatin analogs, peptide receptor radionuclide therapy (PRRT), and targeted therapies. Post-surgical monitoring is adapted according to the original tumor traits and treatment approach. It is advised that regular imaging and biomarker evaluations be conducted to identify any recurrences or advancements in the disease [ 41 ]. Villa et al. (2021) reported a rare appendiceal collision tumor comprising a LAMN and a grade 1 aNET in a 31-year-old woman initially treated for suspected appendicitis. Histological findings prompted a right hemicolectomy due to mesoappendiceal invasion and positive margins, with the case underscoring the importance of multidisciplinary management and individualized surgical strategies for incidental appendiceal neoplasms [ 42 ]. Ahmed et al. (2024) investigated the optimal surgical approach for aNETs measuring 1–2 cm, analyzing data from 3189 patients in the National Cancer Database (2004–2018). Approximately half (50.7%) of the patients underwent appendectomy, while the remainder (49.3%) received the right hemicolectomy. Over time, appendectomy rates significantly increased, from 37.7% in 2004 to 58.9% in 2018. Multivariable analysis indicated that higher tumor grade (G2–G3) was associated with a greater likelihood of right hemicolectomy, whereas longer travel distance correlated with more conservative treatment. Crucially, when adjusting for tumor grade, no survival advantage was observed with hemicolectomy over appendectomy. The study supports a more conservative surgical approach for 1–2 cm aNETs, emphasizing that routine right hemicolectomy may be unnecessary and that treatment decisions should be guided by tumor biology and patient-specific factors [ 43 ]. Sadot et al. concluded that laparoscopy offers diagnostic effectiveness comparable to open surgery; however, visual inspection alone is unreliable for ruling out underlying pathology [ 33 ]. They recommend routine HP evaluation of all resected appendices and emphasize the need for cautious surgical planning, particularly in the presence of identified risk factors. Uri and Grozinsky-Glasberg (2018) provided a comprehensive review of current therapeutic strategies for advanced GEP-NETs, emphasizing a multidisciplinary, individualized approach based on tumor grade, differentiation, and somatostatin receptor expression [ 44 ]. First-line treatment typically involves somatostatin analogs (e.g., Octreotide, Lanreotide), with subsequent options such as PRRT, targeted agents (Everolimus, Sunitinib), or chemotherapy tailored to tumor biology and progression, underscoring the value of integrating clinical and molecular data in treatment planning. The management of aNETs should be individualized based on tumor size, grade, mesoappendiceal invasion, and resection margins, with strong evidence supporting a conservative approach for 1–2 cm lesions, as routine right hemicolectomy offers no significant survival advantage. Survival outcomes in aNET patients are influenced by both biological and demographic factors, and personalized treatment strategies, including somatostatin analogs, PRRT, and targeted therapies, combined with tailored postoperative surveillance and multidisciplinary care, are essential to optimize outcomes and reduce disparities in access to care.

Although aNETs are rare, their incidence has risen significantly in recent years due to improved imaging modalities and routine HP analysis of appendectomy specimens, with most cases discovered incidentally and associated with excellent long-term prognosis. Management should be individualized according to tumor size, histological grade, invasion depth, and surgical margins, with appendectomy alone being appropriate for tumors ≤2 cm without high-risk features, as extended resections have not shown a clear survival benefit. Postoperative follow-up must be risk-adapted, employing advanced imaging and biochemical markers, while a multidisciplinary care model is essential to optimize outcomes and reduce disparities in treatment access.

The authors declare that there is no conflict of interests.

Ozcelik’s retrospective study of 975 appendectomy specimens identified appendiceal neuroendocrine neoplasms (aNENs) in 0.9% of cases, predominantly ≤1 cm and located at the appendix tip. Tumor invasion varied across the muscularis propria, serosa, and mesoappendix. Except for one patient with concurrent colon cancer who progressed and died, all others remained disease-free after a mean 78-month follow-up. The study concludes that aNENs are rare, typically incidental findings, and that tumor size and invasion depth are key factors in determining the need for further surgery [ 45 ]. Volante et al. offer a focused analysis of aNETs, emphasizing their relevance as the most common neoplasm of the appendix and the fifth most frequent GI NET [ 28 ]. The study highlights their favorable prognosis, with a 10-year survival rate exceeding 90% and a metastasis rate less than 10%, supporting appendectomy as an effective curative treatment in most cases. Wang et al. analyzed epidemiological and survival trends of appendiceal tumors in the U.S. from 2000 to 2017, focusing on aNETs, using Surveillance, Epidemiology, and End Results (SEER) data from 13 546 cases [ 46 ]. The incidence of aNETs rose sharply – from 0.03 to 0.90 per 100 000 person-years – mainly due to increased detection of localized, well-differentiated tumors, often in younger, white, and female patients. Unlike other appendiceal malignancies, aNETs showed significant improvements in overall and disease-specific survival, particularly in the latter half of the study period. Most aNETs were treated surgically, with minimal use of chemotherapy [ 46 ]. Similarly, Singh et al. analyzed data from Canada and the U.S. (1992–2016), reporting a substantial increase in malignant appendiceal tumor incidence – 232% in the U.S. and 292% in Canada – most notably among younger individuals with NETs [ 47 ]. As appendectomy rates remained stable, the findings suggest a true rise in incidence, warranting further investigation into underlying etiological factors. Crown et al. in a multicenter study of 61 patients with aNETs, compared outcomes between appendectomy and colon resection [ 29 ]. While colon resection was associated with longer surgeries, greater blood loss, and a higher complication rate (30% vs. 6%), both groups showed similar recurrence-free and OS. These findings suggest that more extensive surgery does not confer a survival benefit and support appendectomy as a sufficient approach in appropriately selected cases [ 48 ]. Nagesh et al. identified age, tumor grade, stage, and chemotherapy as key predictors of reduced survival in aNETs, with higher mortality also observed in men and non-Hispanic Black patients, suggesting healthcare disparities [ 49 ]. The findings support the need for early detection and personalized, biologically informed treatment approaches, potentially enhanced by genetic profiling. Current guidelines recommend somatostatin receptor-based PET imaging, alongside MRI and contrast-enhanced triple-phase CT, for patients with residual disease, aNETs >2 cm, or positive nodal/margin status, to improve metastasis detection [ 28 . Sadot et al. found that 11% of appendices appearing normal during laparoscopy were histologically abnormal, and appendiceal tumors were identified in 1.1% of cases – significantly more common in females and in cases of perforation – highlighting the limitations of visual assessment and the need for routine HP evaluation [ 50 ]. Saponjski et al. demonstrated that somatostatin receptor scintigraphy (SRS) is a highly accurate tool for detecting recurrence or metastasis in patients with aNETs, significantly influencing management decisions in a subset of cases [ 51 ]. Given the favorable prognosis of aNETs – with five-year survival exceeding 90% – the study underscores the importance of individualized follow-up strategies and ongoing surveillance based on tumor characteristics and surgical outcomes. aNETs are rare, often incidental findings with favorable prognosis; tumor size and depth of invasion are critical determinants of management, with simple appendectomy being curative for lesions ≤2 cm lacking high-risk features. The rising incidence of aNETs, particularly among younger individuals, suggests improved detection and possibly evolving etiological factors; in the absence of clear survival benefits from extended resections, current guidelines support conservative, individualized management based on HP and imaging criteria. Follow-up intervals and methods should be tailored according to tumor grade and the therapeutic approach. Recommended imaging modalities include contrast-enhanced CT, MRI, and somatostatin receptor-based Dotatate PET–CT for high-risk cases. Biochemical monitoring may involve NE biomarkers such as CgA and neuron-specific enolase (NSE), with surveillance typically conducted every six to 12 months based on individual risk stratification.

Appendiceal neoplasms are broadly classified into three principal HP categories: neuroendocrine tumors (NETs), mesenchymal tumors, and epithelial neoplasms. As delineated in the World Health Organization (WHO) Classification, aNETs encompass well-differentiated carcinoid tumors and neuroendocrine carcinomas (NECs) [ 9 ]. Carcinoid tumors, although uncommon, are the most frequently encountered appendiceal neoplasms, typically originating in the distal third of the appendix. Histologically, they are characterized by low mitotic indices, absence or minimal necrosis, and limited angioinvasion or peritoneal dissemination. Mesenchymal tumors of the appendix, though exceedingly rare, include GI stromal tumors (GISTs), leiomyosarcomas, liposarcomas, and myxomas. Epithelial neoplasms comprise a spectrum ranging from benign lesions to malignant entities, with mucinous neoplasms and well-differentiated adenocarcinomas representing the predominant subtypes [ 10 ]. Malignant tumors of the appendix are significantly less common than colorectal carcinomas (CRCs), representing approximately 0.24% to 0.52% of all GI tract neoplasms. These tumors encompass a broad HP spectrum, often posing diagnostic challenges for pathologists. While conventional colorectal-type adenocarcinomas may occasionally occur in the appendix, appendiceal neoplasms more commonly display distinct morphological features, with AMNs being a characteristic example [ 11 ]. Appendiceal tumors may be classified as primary, originating from the appendix itself, or secondary, arising from peritoneal spread of malignancies within the abdominal or pelvic cavity. Although rare, clinically relevant appendiceal lesions include both neoplastic and non-neoplastic entities. Non-neoplastic findings, often incidental, encompass appendicitis and diverticula, while neoplastic tumors include mesodermal-origin sarcomas, neuroectodermal carcinoids, and, most commonly, epithelial neoplasms derived from the appendiceal mucosa [ 12 ]. Acute appendicitis remains a common surgical emergency in Western countries, where neoplastic appendiceal tumors are identified in 1–8% of appendectomy specimens, most often as incidental findings, with carcinoid tumors being the predominant type and typically exhibiting indolent behavior unless larger than 1 cm. Mucinous neoplasms, including mucinous cystadenomas, low-grade AMNs (LAMNs), and high-grade AMNs (HAMNs), represent the second most frequent subtype and may present with pseudomyxoma peritonei (PMP) or, less commonly, with complications such as mucinous ascites, biliary obstruction, or intestinal blockage [ 13 ].