Published online Aug 26, 2026. doi: 10.12998/wjcc.123303
Revised: June 18, 2026
Accepted: August 5, 2026
Published online: August 26, 2026
Processing time: 96 Days and 20.6 Hours
Large cell neuroendocrine carcinoma (LCNEC) of the extrahepatic bile duct is an exceedingly rare and highly aggressive malignancy, accounting for < 0.2% of all extrahepatic bile duct tumors. Preoperative diagnosis is challenging, and early recurrence is common even after R0 resection. No standard treatment regimen has been established to date. Mismatch repair (MMR) status has important impli
A 73-year-old man presented with obstructive jaundice. Imaging revealed a distal common bile duct mass. After percutaneous transhepatic cholangial drainage for biliary decompression, laparoscopic pancreaticoduodenectomy was performed. Pathological analysis confirmed LCNEC with a minor adenocarcinoma compo
Biliary LCNEC is a rare and aggressive tumor. The pMMR/MSS phenotype provides a molecular rationale for excluding immunotherapy and directs treatment toward platinum-based chemotherapy. Even with a positive margin (R1), individualized adjuvant EP chemotherapy can achieve short-term disease-free survival. Multidisciplinary-guided, molecularly driven individualized therapy is central to the management of such rare malignancies.
Core Tip: This case report describes a distal common bile duct large cell neuroendocrine carcinoma (LCNEC) with a positive bile duct margin (R1 resection). Comprehensive immunohistochemistry revealed a proficient mismatch repair (MMR)/mi
- Citation: Zheng BQ, Wang ZP, Feng RZ, Zheng ZC, Wang HJ, Wang H, Tuo HF. Large cell neuroendocrine carcinoma of the distal common bile duct: A case report and literature review. World J Clin Cases 2026; 14(24): 123303
- URL: https://www.wjgnet.com/2307-8960/full/v14/i24/123303.htm
- DOI: https://dx.doi.org/10.12998/wjcc.123303
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from peptidergic neurons and neuroendocrine cells, most commonly found in the gastrointestinal tract and pancreas[1,2]. Primary NENs of the biliary system are exceedingly rare, accounting for < 0.5% of all gastroenteropancreatic NENs. Among these, poorly differentiated neuroendocrine carcinoma (NEC) represents only 0.19% of extrahepatic bile duct malignancies[1].
According to the World Health Organization (WHO) 2019/2022 classification of digestive system tumors, NENs are categorized into well-differentiated neuroendocrine tumors (NETs), poorly differentiated NEC, and mixed neuroendocrine/non-NEN. Biliary NEC is further subdivided into small cell NEC and large cell NEC (LCNEC); both of which display highly aggressive behavior with early lymph node metastasis and distant spread[3].
Preoperative diagnosis of biliary NEC is difficult. The clinical presentation (obstructive jaundice and abdominal pain) overlaps with that of bile duct adenocarcinoma. Nechi et al[4] reported that most patients lack typical early clinical symptoms; upper abdominal discomfort, pain, and jaundice are the primary reasons for seeking medical attention, with obstructive jaundice as the initial symptom in 56% of patients. Conventional imaging lacks specificity, and endoscopic biopsy frequently yields false-negative results because the tumor is located in the submucosa, covered by normal epithe
At the molecular level, NEC is characterized by frequent TP53 (about 85.8%) and RB1 (about 38.7%) mutations[7]. Mismatch repair (MMR) status is equally critical: As reported by Kasi et al[8] and Marabelle et al[9], most NECs exhibit a proficient MMR (pMMR)/microsatellite stable (MSS) phenotype; a “cold tumor” phenotype with intrinsic resistance to immune checkpoint inhibitors (ICIs). Therefore, MMR status testing is essential for treatment decision-making; pMMR tumors do not respond to ICIs.
Currently, there is no standard treatment regimen for biliary NEC. Surgical resection remains the first-line option. However, according to Kim et al[10], the recurrence rate exceeds 70% even after R0 resection, with a median overall survival of only 9-15 months. Sorbye et al[11] applied platinum-based chemotherapy [(etoposide plus (EP)] to patients with gastrointestinal NEC (WHO G3), drawing on experience from small cell lung cancer, but evidence for its use in biliary NEC remains limited.
A 73-year-old man was admitted to the outpatient clinic of the Department of Hepatobiliary and Pancreatic Surgery, Hebei General Hospital in March 2025, presenting with a 3-day history of intermittent right upper abdominal pain, accompanied by progressive jaundice of the skin and sclera, and low-grade fever (maximum 37.8 °C).
The above symptoms began 3 days prior to admission. The pain was described as an intermittent dull ache located in the right upper quadrant without radiation. The jaundice progressively worsened, accompanied by dark urine and pruritus. The patient denied nausea, vomiting, or weight loss.
The patient had no prior medical history of hepatitis, diabetes mellitus, hypertension, or surgery. He denied alcohol consumption and smoking.
The patient denied any family history of malignancy or hereditary tumor syndromes.
Vital signs on admission: Body temperature 37.8 °C, blood pressure 135/82 mmHg, heart rate 88 beats/minute, and respiratory rate 18 breaths/minute. Physical examination revealed marked jaundice of the skin and sclera. The abdomen was flat and soft, with mild tenderness in the right upper quadrant but no guarding or rebound tenderness. Murphy’s sign was negative. No abdominal masses were palpable. Bowel sounds were normal.
Admission laboratory investigations: Total bilirubin 224.2 μmol/L (normal range: 3.4-20.5 μmol/L), direct bilirubin 150.8 μmol/L (0-6.8 μmol/L), alanine aminotransferase 58.6 U/L (10-40 U/L), aspartate aminotransferase 52.3 U/L (10-40 U/L), alkaline phosphatase 212 U/L (40-130 U/L), and γ-glutamyl transferase 189 U/L (8-58 U/L). Tumor markers: Carcinoembryonic antigen 2.67 μg/L (0-5 μg/L), α-fetoprotein 3.62 μg/L (0-7 μg/L), and carbohydrate antigen (CA)19-9 > 1000 U/mL (0-37 U/mL). Complete blood count showed mild leukocytosis (white blood cell count 12.07 × 109/L, normal range: 3.5 × 109-9.5 × 109/L). Hepatitis B and C serology was negative.
Contrast-enhanced abdominal computed tomography (CT) revealed thickening of the distal common bile duct wall with luminal narrowing and marked dilatation of the upstream intrahepatic and extrahepatic bile ducts (maximum diameter 16 mm). Magnetic resonance cholangiopancreatography (MRCP) demonstrated segmental interruption of the middle and distal common bile duct, with a nodular, slightly hyperintense signal on T2-weighted imaging measuring 16 mm × 14 mm (Figure 1A). Abdominal contrast-enhanced magnetic resonance imaging (MRI) in the arterial phase (LAVA+C sequence) showed a markedly heterogeneous enhancing nodular mass of approximately 16 mm × 14 mm in the distal common bile duct (Figure 1B), with rapid washout in the portal venous/delayed phase (Figure 1C). This hypervascular enhancement pattern differed from the progressive delayed enhancement typical of cholangiocarcinoma, raising the possibility of a NET. Chest CT revealed no pulmonary or mediastinal abnormalities. No distant metastasis was detected.
Following admission, a multidisciplinary team (MDT) comprising hepatobiliary and pancreatic surgery, medical oncology, gastroenterology, radiology, ultrasound, interventional radiology, and pathology, conducted a systematic case discussion. The consensus was as follows: (1) Based on imaging findings and the markedly elevated CA19-9, the most likely diagnosis was distal bile duct carcinoma. Clinical staging [American Joint Cancer Committee (AJCC), 8th edition] was cT2N0M0, stage IIA. However, contrast-enhanced MRI features raised the suspicion of a NET; (2) In view of the severe obstructive jaundice and Child–Pugh class B (score 8), percutaneous transhepatic cholangial drainage (PTCD) was recommended to relieve jaundice and improve liver function before radical surgery; (3) Once liver function improved, laparoscopic pancreaticoduodenectomy (LPD) was planned as the curative procedure, with systematic lymphadenectomy of stations 8, 12, 13, and 16; and (4) The resected specimen should undergo comprehensive immunohistochemical ana
Following the availability of postoperative pathological findings, the MDT reconvened to formulate an adjuvant treat
LCNEC of the distal common bile duct, with a minor adenocarcinoma component (< 10%, consistent with LCNEC). Pathological stage: PT2N0M0, stage IIA (AJCC 8th edition, distal bile duct staging system).
The patient had an uneventful postoperative recovery and was discharged on postoperative day 12. Adjuvant EP chemotherapy was initiated on May 13, 2025. The regimen for each cycle was as follows: Etoposide 0.1 g intravenously on days 1-3 and cisplatin 20 mg intravenously on days 1-5; the drugs were administered on days 1, 2, and 3 of each cycle, followed by a rest and recovery period, with cycles repeated every 3 weeks. The patient completed a total of six cycles (May 13 to August 31, 2025). Chemotherapy was well tolerated, with only grade 1 nausea and mild fatigue, requiring neither dose reduction nor treatment delay.
Follow-up contrast-enhanced abdominal CT performed after completion of chemotherapy (September 15, 2025) showed postoperative changes consistent with LPD. No local recurrence, hepatic metastasis, or lymphadenopathy was observed. The tumor marker CA19-9 decreased to 26.5 U/mL (within normal range). The patient was followed up regularly. At the most recent follow-up (April 25, 2026, 12 months postoperatively), the patient is alive and asymptomatic. Follow-up will continue every 3 months. The clinical timeline is illustrated in Figure 3.
The diagnostic process of this case exemplifies an evidence-based clinical approach grounded in comprehensive clinical information. The patient presented with obstructive jaundice, right upper quadrant abdominal pain, and low-grade fever; a symptom complex highly suggestive of malignant biliary obstruction. Non-contrast CT showed thickening of the distal common bile duct wall with upstream biliary dilatation, and both MRCP and contrast-enhanced MRI clearly demon
In establishing the diagnosis of primary biliary LCNEC, several entities must be excluded: (1) Poorly differentiated adenocarcinoma: The dominant histological pattern in this case was LCNEC (> 90%), confirmed by diffuse positivity for Syn and CgA, and a Ki-67 index of 60%. Poorly differentiated adenocarcinomas typically express CK7, CK20, and CDX2 without diffuse neuroendocrine marker expression; (2) Metastatic NEC from the lung or other sites: Preoperative chest CT showed no pulmonary mass, and the presence of an overlying high-grade intraepithelial neoplasia supported a primary biliary origin; and (3) Lymphoepithelioma-like carcinoma: This entity is characterized by nests of undifferentiated cells with dense lymphoplasmacytic infiltrate and Epstein-Barr virus association, neither of which was observed. Other rare biliary malignancies, such as clear cell carcinoma or sarcomatoid carcinoma, were excluded based on the absence of their respective morphological and immunohistochemical features.
The role of MMR status represents one of the key contributions in this case. The tumor expressed all four MMR proteins, indicating a pMMR/MSS phenotype. Tumors with pMMR display a low tumor mutational burden and a limited neoantigen load, thereby forming a noninflamed (cold) tumor microenvironment, and their objective response rate to ICIs is typically < 5%[9,12,20]. Conversely, deficient MMR/high microsatellite instability tumors, due to their high mutational burden, are highly sensitive to ICIs, with objective response rates reaching 30%-50%[22]. The definitive finding of pMMR in this patient enabled the team to exclude immunotherapy and concentrate on cytotoxic chemothe
NEC is characterized by high-frequency mutations in TP53 and RB1. In pulmonary LCNEC, RB1 mutation or loss of expression predicts greater sensitivity to SCLC-like regimens (EP platinum)[23]. International guidelines (National Comprehensive Cancer Network and European Society for Medical Oncology) recommend platinum-based combination chemotherapy for high-grade NEC. The NORDIC NEC study demonstrated that the EP regimen (EP cisplatin) achieves a superior objective response rate in gastroenteropancreatic NEC with Ki-67 > 55%[11], and RB1-mutant pulmonary LCNEC is similarly sensitive to such SCLC-like regimens[23]. The choice of EP in this case is based on the following factors: (1) The Ki-67 index of approximately 60%, matching the EP-favored population; (2) Cisplatin is the standard agent in pivotal studies like NORDIC, with stronger evidence in NEC than carboplatin or gemcitabine plus cisplatin; and (3) With an ECOG performance status of 0 and normal renal function, the MDT established a specific dosing schedule (etoposide 0.1 g on days 1-3, cisplatin 20 mg on days 1-5, every 3 weeks) to balance efficacy and safety. Prospective data for biliary tract NEC remain limited, and the optimal platinum-based regimen awaits further investigation.
Traditional biliary oncology emphasizes the prognostic value of R0 resection. This case challenges that tenet: In the context of NEC, the patient achieved 12-month disease-free survival despite a positive hepatic duct margin. The likely explanation lies in the systemic nature of NEC; even patients with apparently localized disease on imaging may harbor radiographically occult micrometastases. The literature indicates that recurrence predominantly manifests as distant metastasis (liver, lung, and peritoneum) and occurs within 3-6 months postoperatively[3,10,14,15]. Therefore, for biliary NEC, effective systemic therapy may outweigh margin status in prognostic importance. Surgery should aim to relieve biliary obstruction, obtain tissue for pathological and molecular classification, and achieve macroscopic tumor clearance when feasible. Adjuvant chemotherapy such as EP should be initiated as early as possible postoperatively, regardless of margin status, provided the patient’s general condition permits.
This case fully exemplifies the central role of the MDT in managing rare malignancies (Table 1). From preoperative staging decisions and surgical planning to the postoperative formulation of chemotherapy based on MMR status, the MDT made decisive contributions at multiple critical junctures. Without MDT involvement, the molecular information regarding pMMR might have been overlooked, and the patient may have received ineffective immunotherapy or no systemic treatment at all. The MDT workflow integrating molecular pathology demonstrated in this case is generalizable to the management of other rare tumors.
| Treatment stage | Core contributions of MDT |
| Diagnosis | Department of Radiology and Ultrasound interpreted the “fast-in, fast-out” imaging features of the lesion, suggesting the possibility of a neuroendocrine tumor |
| Preoperative | Department of Interventional Radiology performed percutaneous transhepatic cholangiography and drainage to ensure surgical safety; the Department of Surgery formulated the surgical plan for laparoscopic pancreaticoduodenectomy |
| Pathology | Comprehensive immunohistochemical tests (including MMR protein testing) were performed, confirming proficient MMR and excluding indications for immunotherapy |
| Adjuvant therapy | Department of Medical Oncology formulated the EP regimen; the Department of Pathology reconfirmed no indications for immune checkpoint inhibitor therapy |
| Follow-up | Multidisciplinary coordination completed imaging reexamination and clinical efficacy evaluation |
To our knowledge, this is the first biliary LCNEC case in which MMR status directly informed the exclusion of immunotherapy. The pMMR/MSS phenotype predicts poor ICI response, with a response rate consistently below 5% in colorectal and gastroesophageal adenocarcinomas[9,12], although dedicated data for biliary NEC are lacking. Our decision rested on three considerations. First, intact MMR protein expression indicated a low tumor mutational burden and a non-inflamed (“cold”) tumor microenvironment. Second, high-grade NECs share conserved molecular features across anatomic sites, including frequent TP53/RB1 mutations and a typically “cold” immune landscape[7], allowing reasonable extrapolation from other gastrointestinal NECs. Third, no MSI-H/dMMR case has been reported among all biliary NECs tested to date[19], further arguing against ICI benefit. However, the current evidence remains indirect, and prospective studies are required to validate pMMR/MSS as a predictive biomarker specifically in biliary NEC (Table 2).
| Ref. | Age (year) | Sex | Histology | Surgical procedure | Resection margin | Adjuvant chemotherapy | Overall survival (months) | Outcome |
| Sasatomi et al[3], 2013 | 76 | M | LCNEC (pure) | Right hepatectomy + bile duct resection | R0 | None | < 1 (21 days) | DOD |
| Kamiya et al[6], 2020 | 84 | M | NEC with adenosquamous ca. (MiNEN) | Pancreaticoduodenectomy | NR | No (rapid progression) | 3 | DOD |
| Kim et al[10], 2011 | 66 | F | NEC (gallbladder) | Extended cholecystectomy | R0 | None | 13.7 | DOD |
| Kim et al[10], 2011 | 69 | M | NEC (bile duct) | Pancreaticoduodenectomy | R0 | NR | 11.6 | DOD |
| Kim et al[10], 2011 | 56 | M | NEC (ampulla) | Pancreaticoduodenectomy | R0 | None | > 102.1 | NED |
| Kim et al[10], 2011 | 60 | F | MANEC (gallbladder) | Extended cholecystectomy | R0 | NR | 33.9 | DOD |
| Kim et al[10], 2011 | 54 | M | MANEC (bile duct) | Pancreaticoduodenectomy | R0 | NR | 5.2 | DOD |
| Murakami et al[14], 2016 | 80 | M | LCNEC + Adenoca. (MiNEN) | Extrahepatic bile duct resection | R0 | No (poor condition) | 3 | DOD |
| Park et al[15], 2014 | 75 | F | LCNEC (pure) | CBD excision + HJ | R0 | 5-FU + epirubicin + cisplatin | 12 | DOD |
| Park et al[17], 2022 | 60 | F | LCNEC + Adenoca. (MiNEN) | Left hepatectomy + caudatectomy | NR | EP × 6 cycles | 7+ | NED |
| Park et al[17], 2022 | 67 | M | LCNEC + Adenoca. (MiNEN) | PPPD | NR | EP × 6 cycles | 7+ | NED |
| Sato et al[18], 2006 | 68 | M | LCNEC + Adenoca. (MiNEN) | Pancreaticoduodenectomy | NR | NR | 3 | DOD |
| Liu et al[19], 2026 | 63 | M | SCNEC (distal bile duct) | Pancreaticoduodenectomy | R0 | EP (after recurrence) | 25.3 (759 days) | DOD |
| Liu et al[19], 2026 | 77 | M | SCNEC (distal bile duct) | Pancreaticoduodenectomy | R0 | None | 22.5 (674 days) | DOD |
| Liu et al[19], 2026 | 61 | M | LCNEC (gallbladder) | Cholecystectomy + IVb/V resection | R0 | EP (after recurrence) | 10.1 (302 days) | DOD |
| Liu et al[19], 2026 | 57 | F | SCNEC (gallbladder) | Cholecystectomy + IVb/V resection | R1 | None | 7.7 (230 days) | DOD |
| Liu et al[19], 2026 | 72 | F | SCNEC (gallbladder) | Cholecystectomy + IVb/V resection | R0 | None | 26.0 (781 days) | DOD |
| Liu et al[19], 2026 | 67 | F | SCNEC (gallbladder) | Cholecystectomy + IVb/V resection | R0 | None | 15.5 (465 days) | DOD |
| Liu et al[19], 2026 | 65 | F | LCNEC (hilar) | CBD resection + HJ | R0 | None | 20.8 (624 d) | DOD |
| Liu et al[19], 2026 | 67 | F | SCNEC (hilar) | CBD resection + HJ | R0 | None | 31.8 (953 days) | DOD |
| Liu et al[19], 2026 | 57 | F | NR (hilar) | CBD resection + HJ | R0 | None | 2.2 (67 days) | Alive |
| Zhang et al[16], 2025 | 75 | M | LCNEC + Adenoca. (MiNEN) | Laparoscopic radical resection | R0 | Declined | 6 (then recurrence) | AWD |
| Park et al[20], 2018 | 59 | M | LCNEC (pure) | Radical CBD excision + HJ | R1 | EP + radiotherapy | 10+ | NED |
| Present case (2026) | 73 | M | LCNEC + Adenoca. (MiNEN) | Laparoscopic PD | R1 (bile duct) | EP × 6 cycles | 12+ | NED |
The strengths of the study were as follows: (1) This is the first explicitly documented case in biliary LCNEC of MMR testing directly influencing treatment decisions; (2) It demonstrates that with effective systemic therapy, short-term progression-free survival can still be achieved despite R1 resection; and (3) It presents in detail an MDT workflow that is generalizable to other rare tumors.
This study had some limitations: (1) The follow-up duration was short (12 months); (2) Long-term survival and recurrence risk remain undefined; (3) Conclusions regarding causality cannot be drawn from a single case; (4) RB1 mu
This case highlights the pivotal role of molecular pathology in guiding individualized treatment for rare biliary NENs. The identification of a pMMR/MSS phenotype provided a molecular rationale for excluding ICI and directing therapy toward platinum-based chemotherapy, which resulted in sustained 12-month disease-free survival. The key clinical implications are as follows: (1) MMR status should be routinely assessed in all biliary NECs, as patients with pMMR/MSS tumors are unlikely to benefit from ICIs; (2) Effective systemic therapy is critical for improving outcomes and should not be deferred due to margin status; and (3) MDT integration of molecular pathology represents the core model for managing rare tumors and is generalizable to other rare malignancies. Prospective studies are warranted to further vali
The authors thank all members of the hepatobiliary tumor multidisciplinary team at Hebei General Hospital for their dedicated collaboration, and the patient for his trust and cooperation.
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