Biliary neuroendocrine tumors: a narrative review of current diagnostics and management strategies

Introduction

NETs are a heterogeneous group of neoplasms arising from neuroendocrine cells found throughout the body. While gastroenteropancreatic (GEP) NETs are the most common, accounting for a significant proportion of all NETs, those originating in the biliary tract are exceptionally rare. They represent less than 1% of all GEP-NETs (1). A recent study reported that extrahepatic bile duct neuroendocrine tumors (EBNETs) represent approximately 0.2% to 2% of all gastrointestinal NETs and up to 2% of all malignant tumors of the extrahepatic bile ducts (2). While some of these are often discovered incidentally during surgical procedures for unrelated conditions, such as cholecystitis or cholelithiasis, the non-specific presentation contributes to diagnostic delays and challenges in establishing standardized management protocols (1). Biliary NETs can arise from any part of the biliary tree, including the gallbladder, extrahepatic and intrahepatic bile ducts, and ampulla of Vater (1). Their clinical presentation is often non-specific, mimicking more common benign or malignant biliary etiology, such as cholecystitis or cholangiocarcinoma. This causes early and accurate diagnosis difficult (3). Difficulties in epidemiological reporting on biliary NETs are mainly due to their low numbers and the difficulties in accurately identifying them (4). The mean age of presentation is typically in the fifth to seventh decades, and there appears to be no significant gender predilection. Prognosis often correlates with tumor grade, differentiation, and the presence of metastatic disease at diagnosis, which is unfortunately common due to late presentation (5). This review aims to synthesize and critically evaluate the current evidence on biliary tract NETs, providing a structured narrative overview of their epidemiology, diagnostic pathways, therapeutic strategies, and clinical outcomes. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-76/rc).

Methods

A comprehensive literature search was conducted across PubMed/MEDLINE, Embase, Scopus, Web of Science, and Google Scholar to identify published studies on biliary NETs. The search covered publications from 2010 through February 2025 and incorporated both MeSH terms and free-text keywords related to biliary NETs, diagnostic modalities, pathology, and treatment strategies (Table 1). Additional sources were identified through manual reference screening of key articles. After removal of duplicates, 112 records underwent title and abstract screening, followed by full-text review of 60 articles. Studies were included if they provided clinical, diagnostic, therapeutic, or prognostic information relevant to biliary NETs; non-English articles, conference abstracts without full data, preclinical studies, and papers lacking clinical relevance were excluded. Study selection was performed independently by two reviewers, with discrepancies resolved by consensus. A total of 28 studies were included in the qualitative synthesis. The PRISMA flow diagram is provided in Figure 1.

Figure 1 PRISMA flow diagram of study selection. A systematic literature search conducted between January 2024 and February 2025 identified 112 records. After title and abstract screening, 44 records were excluded, and 68 full-text articles were assessed for eligibility. Of these, 40 were excluded (non-clinical studies, n=14; abstracts only, n=12; insufficient data, n=14). A total of 28 studies met inclusion criteria and were included in the final analysis.

Clinical presentation and diagnosis

The clinical presentation of biliary NETs is often non-specific, with vague abdominal pain being the most common initial symptom. Other non-specific symptoms include obstructive jaundice, weight loss, ascites, pruritus, or a palpable mass. Rarely, endocrine manifestations may occur. This leads to delayed diagnosis, as they can mimic other gallbladder pathologies such as cholecystitis or adenocarcinoma (1,6). Some cases are diagnosed postoperatively on histological evaluation of surgical specimens (7). The diagnosis of biliary NETs is primarily made through histopathological and immunohistochemical examination of surgical specimens (8). Common imaging techniques, such as ultrasound or computed tomography (CT), are insufficient for definitive diagnosis due to the non-specific appearance of these tumors (1). Although grouped under the umbrella term “biliary NETs”, tumors arising from the gallbladder, extrahepatic bile ducts, intrahepatic ducts, and ampulla of Vater exhibit distinct clinical behaviors.

Gallbladder NETs are frequently diagnosed incidentally following cholecystectomy and demonstrate a higher proportion of poorly differentiated neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Extrahepatic bile duct NETs often present with obstructive jaundice at smaller tumor sizes due to luminal narrowing. Intrahepatic NETs are rare and may mimic primary hepatic NET or metastatic disease. Ampullary NETs tend to present earlier because of biliary obstruction and may have comparatively better outcomes when detected at low grade.

These site-specific differences as noted in the Table 2 influence surgical approach, lymph node assessment, and prognosis (2,5,9).

Histologically, biliary NETs are made up of uniform cells arranged in nests, trabeculae, or rosettes. The cells show round nuclei with thinly dotted chromatin and medium-colored cytoplasm. However, high-grade NECs are characterized by nuclear atypia, increased cell division, and regular necrosis (9). The exact cellular derivation of the biliary neuroendocrine tumours is still subject to intense controversy. Several hypotheses have been proposed such as the existence of scarce neuroendocrine cells, which have been housed within the peribiliary glands, the neuroendocrine metaplasia of the biliary epithelial cells, which is a result of chronic inflammatory stimuli like cholelithiasis or cholangitis, and divergent differentiation that is a result of pluripotent biliary epithelial stem cells. The low density of the neuroendocrine cells in bile duct epithelium is exceptionally low and the case series has been used to implicate either metaplastic or stem-cell-derived origins of biliary NEC cohorts, but these cohorts are poorly characterised (10). The existing molecular evidence on the biliary neuroendocrine tumours is limited, and most of the information is projected on GEP neuroendocrine neoplasms. TP53 mutations and RB1 loss are characteristic of high-grade NECs and is a molecular signature similar to small-cell carcinomas and unlike well-differentiated neuroendocrine tumours. The latter group is traditionally free of these changes but is often mutated in genes like MEN1, DAXX, ATRX, and varies according to the location of the tumour (11). SSTR2 is the most commonly expressed receptor type in well-differentiated NETs and the basis of the therapeutic effects of somatostatin analogues (SSA), radioligand imaging and peptide receptor radiotherapy (PRRT). SSTR2 expression (more than 70 percent) is associated with high-quality imaging fidelity and targeting of therapies in well-differentiated NETs. Poorly differentiated NECs, in their turn, have significantly weakened or no SSTR2 expression, which explains the reduced effectiveness of PRRT in the stated category (12).

MiNENs is a unique pathological phenomenon in the gallbladder and extrahepatic bile ducts. These lesions have morphological components of neuroendocrine and adenocarcinoma with each component representing at least 30 percent of the tumor mass. Clinical behavior of MiNENs is typically dictated by the most aggressive component, and most often it is the NEC fraction. Therapeutic implications of the identification of a high-grade NEC or MiNEN component. An increased lymphadenectomy to treat possible nodal spread is often required by operative strategy and systemic treatment regimens tend to employ platinum-based combinations similar to those used to treat small-cell carcinoma, unlike the traditional NET regimens. This means that the prognosis of patients with high-grade NEC or MiNEN is significantly worse than the prognosis of patients with well-differentiated NETs (9). To confirm that a tumor is neuroendocrine, IHC staining is very important. Chromogranin A (CgA) and synaptophysin are commonly used to show that a tumor has dense-core granules and synaptic vesicles (3). INSM1, a nuclear transcription factor, is now known to be a highly specific neuroendocrine marker and becomes especially helpful when chromogranin or synaptophysin expression is not clear (13). Ki-67 proliferation index is used as the main tool for grading NETs according to the 2022 World Health Organization (WHO) classification. If the Ki-67 index is less than 3%, the tumor is given grade 1, if it is 3–20%, it is grade 2, and if it is higher than 20%, it is grade 3, with both prognostic and treatment implications (13). Biochemical testing is used together with histology. Even though serum CgA is often raised in NETs, it can also be elevated by using proton pump inhibitors, having renal insufficiency, or having chronic atrophic gastritis Most of the time, urinary 5-HIAA is helpful in diagnosing serotonin-producing NETs, but elevated levels in biliary NETs are rare. Even though molecular profiling is not yet standard for biliary NETs, it is becoming more important. Genetic changes such as MEN1, DAXX, and ATRX, which are common in pancreatic NETs, have been found in biliary tumors only a few times (14). Researchers are exploring ctDNA and CTCs as possible noninvasive methods for detecting biliary NETs early, but their use is not yet confirmed. Imaging helps in both finding out the diagnosis and determining the stage of the cancer. Using contrast-enhanced CT or magnetic resonance imaging (MRI), especially MRCP, allows doctors to outline the tumor, look at nearby vessels, and decide on the best surgery. MRCP+, a quantitative MRCP method, seems to be helpful in telling apart strictures from mass lesions (15).

It is necessary to use functional imaging to confirm neuroendocrine differentiation and determine if the disease has spread throughout the body. Gallium-68 DOTATATE positron emission tomography (PET)/CT is now the main technique for finding NETs that have somatostatin receptors, and it provides better images than previous scintigraphy (16). Because high-grade or poorly differentiated tumors have increased metabolism, 18F-FDG PET/CT is most often used for these cases. Using DOTATATE and FDG imaging together can help determine how varied the cancer is and assist in choosing the best treatment (16). Endoscopic methods, such as endoscopic retrograde cholangiopancreatography (ERCP), can detect intraductal masses and obtain tissue samples for analysis using brush cytology or biopsy. Yet, NETs are not easily detected because they are found under the mucous membrane. Endoscopic ultrasound (EUS) can sample periampullary or extrahepatic lesions very effectively, whether it is used with fine-needle aspiration (FNA) (17). Using probe-based confocal laser endomicroscopy (pCLE) during ERCP, it is now possible to examine the biliary mucosa in real time, and it may help tell the difference between neoplastic and inflammatory strictures (18). The first step in a recommended diagnostic approach is to suspect a disease after observing obstructive jaundice, abdominal pain, or any abnormal imaging findings. The next step is to perform liver function tests, serum CgA, and 5-HIAA if the doctor believes it is necessary. MRI/magnetic resonance cholangiopancreatography (MRCP) or CT is used to see where the lesion is and whether it can be removed. Using DOTATATE and/or FDG PET imaging, it is possible to confirm that the tumor is a NET and to assess disease spread.

Treatment approaches

The management options of biliary NETs are a combination of both operative and nonoperative options.

Surgical management

Operative management mainly involve laparoscopy’s or laparotomy surgery, which is the mainstay, especially in patients without ductal invasion or significant symptoms, enabling the surgeons to do complete resection. The treatment aims to improve the effectiveness of the intervention while preserving the quality of life, but adapting the planned intervention to the patient’s characteristics and the tumor development. Timely diagnosis and treatment of biliary NETs have a significant impact on prognosis. The clinical outcomes for biliary NETs are highly variable and depend on several factors, including tumor grade, stage at diagnosis, completeness of surgical resection, and the availability of effective systemic therapies. Generally, well-differentiated NETs have a more indolent course and better prognosis than poorly differentiated NECs, which are aggressive and associated with significantly shorter survival times (19).

Systemic therapy

Unresectable tumors are managed systemically using SSAs, peptide receptor radionuclide therapy (PRRT), and tyrosine kinase inhibitors (TKIs). These modalities are more effective if tumors are well-differentiated.

SSAs such as octreotide LAR and lanreotide are often the first step. They work by attaching to somatostatin receptors on the tumor cells, slowing down tumor growth and helping manage symptoms caused by hormone secretion. Large studies such as PROMID and CLARINET have shown that these drugs can significantly delay tumor progression, particularly in tumors of the midgut and pancreas (20,21). When tumors continue to grow despite SSA therapy, and especially if they still express somatostatin receptors, PRRT becomes an option. This therapy uses a radioactive version of somatostatin (typically ^177Lu-DOTATATE) to deliver radiation directly to the tumor cells. The NETTER-2 trial demonstrated that PRRT can significantly prolong the median progression-free survival and enhance quality of life (22). TKIs, such as cabozantinib and everolimus, are considered if the patient is refractory to SSA or PRRT (23,24). In many cases, these therapies are used in combination or in sequence to manage NETs in the long term, while minimizing side effects and maintaining quality of life.

It is important to note that biliary NETs were not specifically represented as a predefined subgroup in major randomized trials such as PROMID, CLARINET, NETTER-2, RADIANT-4, or the phase III cabozantinib study. If present, biliary primaries constituted only a negligible proportion within broader GEP NET cohorts and were not reported separately. Therefore, current systemic treatment recommendations for biliary NETs are largely extrapolated from midgut and pancreatic NET data. Given known biological heterogeneity across primary sites, this extrapolation represents a limitation, and therapeutic outcomes specific to biliary NETs remain insufficiently defined.

Prognosis

Although they are uncommon, biliary NETs belong to a special group of GEP neuroendocrine neoplasms and usually start in the extrahepatic bile ducts or gallbladder. The prognosis is primarily affected by the tumor grade, stage at diagnosis, and the possibility of removing the tumor. Grade 1–2 biliary NETs usually have a better outcome than NECs, which are aggressive and tend to grow rapidly (10). Surgery is a definitive curative treatment modality for resectable patients. According to earlier studies, surgical resection of well-differentiated tumors can yield favorable long-term outcomes, with a 5-year survival rate exceeding 70% (25). When lymph nodes are not involved and there are few dividing cells (Ki-67 <10%), the outlook for patients is excellent. However, NECs in the biliary tract, especially those with high Ki-67 levels, typically have a median survival time of 6 to 12 months, regardless of whether they receive systemic chemotherapy. Following complete resection of a well-differentiated biliary NET, 68Ga-DOTATATE PET/CT is recommended for long-term surveillance of patients with NETs (26). Rarely, high-grade transformation can occur, leading to poor clinical outcomes. Tumor grade, the Ki-67 index, and complete tumor resection (R0) are the most important factors for predicting the outcome. Identification of these prognostic factors led to various predictive tools, including normal grams, aiding in better assessment of prognosis (5). A National Cancer Database study reported that primary gallbladder NETs are associated with a poorer prognosis compared to NETs at other gastrointestinal sites. This study reported that the factors associated with decreased survival following resection include older age, positive surgical margins, and large cell histology (16). All these factors could evaluate the treatment decision-making, providing individualized assessment and care.

Challenges and future directions

The rarity of biliary NETs means that it is hard to conduct extensive clinical trials, so data from more common GEP-NETs are often used instead. Since tumors can be either slow-growing or very aggressive, patients diagnosed with biliary NET must be treated in a way that fits their specific needs. Many patients are not diagnosed early because the symptoms are general, and the tumor is hard to locate in the body. Creating new ways to screen for or identifying sensitive, non-invasive markers may help detect cancer earlier. Although molecular diagnostics are improving, we still require reliable biomarkers to support informed treatment decisions and prevent unnecessary treatments. Since these tumors are complex, receiving care at specialized, multidisciplinary NET centers is crucial, and these centers are primarily located in larger academic institutions.

Conclusions

NETs of the biliary tract represent a fascinating and evolving area in gastrointestinal oncology. The diagnosis and management are in line with GEP NETs. The diagnostic accuracy and staging are significantly improved with ⁶⁸Ga-DOTA-SSA PET/CT. Molecular diagnostics are beginning to unravel the intricate genetic landscape, moving towards more personalized therapeutic strategies. The addition of new surgical approaches, effective somatostatin analogs, the introduction of PRRT, and the use of everolimus, sunitinib, and cabozantinib have significantly improved clinical outcomes. Even though these tumors are rare and differ significantly, new studies and constant multidisciplinary teamwork are expected to help patients with biliary NETs experience better outcomes and improved lives. With a deeper understanding of these biliary NETs, their treatment is becoming more accurate and effective.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-76/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-76/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-76/coif). A.M. reports research grant from Astrazeneca. A.K. reports consulting for Ipsen, Cardinal Health, Partner Therapeutics. R.K.P. reports as members of speaker bureau for Exelixis and Ipsen. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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