Biliary neuroendocrine carcinoma (Biliary NEC) is a rare and highly aggressive malignant tumor originating from neuroendocrine cells within the biliary system. Its incidence is extremely low, accounting for less than 1% of all gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), and it most commonly arises in the gallbladder or the common bile duct (1). Because neuroendocrine cells are sparsely distributed in the biliary tract (2), the pathogenesis of Biliary NEC remains poorly understood. Several hypotheses have been proposed, suggesting that it may originate from neuroendocrine metaplasia of the biliary epithelium, clonal evolution of adenocarcinoma, or aberrant differentiation of pluripotent stem cells (3, 4).

Clinically, Biliary NEC lacks specific manifestations. The most common presenting symptoms include upper abdominal pain, obstructive jaundice, and unexplained weight loss. Its imaging features often mimic those of cholangiocarcinoma or gallbladder adenocarcinoma, leading to a high rate of preoperative misdiagnosis (5, 6). Common tumor markers such as CA19-9, CEA, and CA125 are frequently normal or only mildly elevated (7). Therefore, definitive diagnosis typically depends on postoperative histopathological and immunohistochemical findings, including positive staining for markers such as synaptophysin (Syn), chromogranin A (CgA), and CD56 (5, 8).

Histologically, Biliary NEC represents a poorly differentiated and high-grade neuroendocrine neoplasm, which can be classified into small-cell (SCNEC) and large-cell (LCNEC) types. It differs fundamentally from well-differentiated NET G3 in both morphology and biological behavior (4, 9). The characteristic pathological features include marked nuclear atypia, extensive necrosis, frequent mitoses, and a high Ki-67 proliferation index (typically >50%), indicating a highly aggressive biological phenotype (10).

Currently, there is no standardized treatment guideline for Biliary NEC. For patients with resectable disease, radical surgery remains the mainstay of therapy and offers the best chance for long-term survival. Systemic treatment strategies are generally extrapolated from those used for small-cell lung cancer and extrapulmonary NECs, with platinum-based doublet regimens—such as etoposide plus cisplatin (EP) or irinotecan plus cisplatin—being commonly adopted (11, 12). However, most available studies consist of isolated case reports or small case series, and robust evidence regarding surgical indications, systemic chemotherapy strategies, and long-term prognosis remains scarce.

Given its rarity, diagnostic challenges, and therapeutic heterogeneity, Biliary NEC continues to pose a significant clinical challenge. This study retrospectively analyzed patients with pathologically confirmed Biliary NEC who underwent surgical resection at our institution between 2012 and 2025. We aimed to systematically summarize their clinicopathological characteristics, treatment patterns, and survival outcomes, and to compare our findings with those reported in the literature, thereby providing additional evidence for clinical decision-making in this uncommon malignancy.

Biliary neuroendocrine carcinoma (Biliary NEC) is an extremely rare and highly aggressive malignancy, accounting for approximately 0.5% of all neuroendocrine neoplasms (NENs) (27). Due to its low incidence, nonspecific clinical manifestations, and rapid progression, most patients are diagnosed at an advanced stage and consequently miss the optimal window for curative treatment (28–30). Therefore, the overall prognosis of Biliary NEC remains dismal. Although the number of reported cases has gradually increased in recent years owing to advances in immunohistochemistry and imaging technology, large-scale studies are still lacking, and the understanding of this disease remains limited. In this study, we retrospectively analyzed nine cases of pathologically confirmed Biliary NEC treated at our institution over the past decade and compared our findings with previous reports to summarize the clinicopathological characteristics, therapeutic strategies, and prognostic outcomes, thereby enriching current evidence on this rare malignancy.

Consistent with previous studies, patients with Biliary NEC in our cohort had a median age of approximately 60 years and a slight female predominance. Histologically, most tumors were poorly differentiated, either small-cell neuroendocrine carcinoma (SCNEC) or large-cell neuroendocrine carcinoma (LCNEC), with Ki-67 indices commonly exceeding 50%. The clinicopathological and immunophenotypic features in our study—positive expression of Syn, CgA, and CD56—were largely in line with previous observations. The median overall survival (OS) in our series was 649 days (approximately 21 months), comparable to the 25 months reported by Ayabe et al. (31) and 23 months by Zhou et al. (30). However, those studies included some well-differentiated NENs, which may account for their relatively better outcomes (32, 33). In contrast, Karim et al. (34), analyzing 278 cases of gallbladder NEC from the SEER database, reported a median OS of only 9.8 months—significantly shorter than in our study. This discrepancy may be attributed to the fact that all patients in our cohort underwent curative-intent resection, and several received systemic chemotherapy.

Accumulating evidence suggests that systemic chemotherapy, particularly platinum-based regimens, may improve survival in patients with biliary neuroendocrine carcinoma (35–38). Chu et al. (27) reported that postoperative systemic chemotherapy prolonged overall survival by approximately 6.7 months compared with surgery alone, while Lee et al. (39) identified adjuvant chemotherapy as an independent prognostic factor (P = 0.007). Similarly, in our study, patients who received systemic chemotherapy showed a trend toward longer survival compared with those who did not; however, this observation should be interpreted cautiously given the limited sample size and descriptive nature of the analysis.

Although R0 resection is traditionally regarded as a prerequisite for long-term survival in biliary malignancies, accumulating evidence indicates that, in biliary neuroendocrine neoplasms (NENs), margin-negative surgery alone is often insufficient to overcome the intrinsically aggressive tumor biology. Recent population-based and multi-institutional studies have shown that patients with biliary NENs are frequently diagnosed at advanced stages and exhibit high proliferative indices, nodal involvement, or distant metastases, ultimately resulting in poor median overall survival despite relatively high rates of R0 or radical resection (12, 30, 40). In these cohorts, survival outcomes were primarily determined by histologic grade, tumor stage, Ki-67 index, and the receipt of systemic chemotherapy rather than by surgical margin status alone, supporting the notion that biliary neuroendocrine carcinoma (NEC) behaves as a systemic disease in many patients at presentation (30, 35, 41). In our series, eight of nine patients achieved R0 resection; however, the median overall survival was only 21 months, and eight patients died during follow-up, further underscoring that tumor biology and treatment strategy may play a more decisive prognostic role than surgical radicality alone.

From a biological perspective, the histologic and molecular characteristics of Biliary NEC closely resemble those of small-cell and large-cell carcinomas. However, the biliary tract itself lacks native neuroendocrine cells, and thus the origin of Biliary NEC remains controversial. The most accepted hypothesis posits that Biliary NEC arises from pluripotent stem cells within the biliary epithelium that undergo neuroendocrine differentiation, or from metaplastic transformation under chronic inflammatory stimulation such as cholelithiasis (29, 34, 42). Another theory proposes that Biliary NEC may develop through “dedifferentiation” of pre-existing adenocarcinoma, in which glandular epithelial cells acquire neuroendocrine features under specific molecular signaling pathways. Regardless of the mechanism, Biliary NEC is characterized by high invasiveness, early local invasion, and a strong propensity for distant metastasis, which collectively explain its aggressive biological behavior and poor clinical outcome.

Previous studies have consistently demonstrated that high-grade histology, elevated Ki-67 index, lymph node metastasis, and lack of systemic chemotherapy are key predictors of unfavorable prognosis in biliary neuroendocrine neoplasms (NENs) (43, 44). Among these factors, Ki-67 is particularly informative because it reflects proliferative activity and correlates with metastatic potential, treatment response, and overall survival in high-grade NENs, and is therefore recommended for risk stratification in clinical practice (45). Lymph node metastasis similarly reflects systemic dissemination and has been associated with significantly reduced postoperative survival in several multicenter and SEER-based analyses. Furthermore, multiple retrospective series have suggested that platinum-based systemic chemotherapy may confer survival benefits, particularly in poorly differentiated biliary neuroendocrine carcinoma (NEC), supporting a treatment paradigm analogous to that used for small-cell lung cancer (46). In our series, four of nine patients had lymph node metastasis and most patients with high Ki-67 indices experienced early death, whereas those who received systemic chemotherapy showed a trend toward longer survival, aligning with previous findings despite the descriptive nature of our cohort.

Nevertheless, several limitations should be acknowledged. First, the small sample size limits the statistical power of our analysis and precludes multivariate survival analysis. Second, detailed data on chemotherapy regimens, cycles, and recurrence patterns were incomplete for some cases. Third, molecular and immunogenomic analyses were not performed, preventing exploration of potential genetic alterations or immune microenvironmental factors influencing disease behavior. Future multicenter collaborations and establishment of dedicated databases for biliary neuroendocrine tumors are warranted to achieve a more comprehensive understanding of this disease. Integrating molecular profiling and immunological characterization may further refine risk stratification and facilitate the development of individualized therapeutic strategies.

In summary, this study reviewed nine cases of biliary neuroendocrine carcinoma (Biliary NEC) diagnosed and treated at our institution over the past decade. Biliary NEC predominantly affects elderly women and is characterized by nonspecific clinical manifestations, leading to diagnostic challenges. Histopathological and immunohistochemical evaluations remain essential for definitive diagnosis. Surgical resection remains the cornerstone of curative treatment, while systemic chemotherapy may provide additional survival benefit in selected patients.

Despite the limited sample size, our findings highlight the importance of early recognition, aggressive surgical management, and appropriate systemic therapy in improving patient outcomes. Future multicenter studies with larger cohorts and integrated molecular analyses are warranted to elucidate the biological characteristics of Biliary NEC and to develop more precise, individualized therapeutic strategies.