Neuroendocrine carcinoma (NEC) of the extrahepatic bile duct is very rare, and the treatment and prognosis are unclear. Herein, we report the case of a middle-aged female with primary large cell NEC (LCNEC) of the common hepatic duct combined with distal cholangiocarcinoma (dCCA). Additionally, after a review of the relevant literature, we summarize and compare mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and pure NEC to provide a reference for selecting the appropriate treatment and predicting the prognosis of this rare disease.

A 62-year-old female presented to the hospital due to recurrent abdominal pain for 2 months. Physical examination showed mild tenderness in the upper abdomen and a positive Courvoisier sign. Blood tests showed elevated liver transaminase and carbohydrate antigen 199 levels. Imaging examination revealed a 1-cm tumour in the middle and lower segments of the common bile duct. Pancreaticoduodenectomy + lymph node dissection was performed, and hepatic duct tumours were unexpectedly found during surgery. Pathology suggested poorly differentiated LCNEC (approximately 0.5 cm × 0.5 cm × 0.4 cm), Ki-67 (50%), synaptophysin+, and chromogranin A+. dCCA pathology suggested moderately differentiated adenocarcinoma. The patient eventually developed lymph node metastasis in the liver, bone, peritoneum, and abdominal cavity and died 24 months after surgery. Gene sequencing methods were used to compare gene mutations in the two primary bile duct tumours.

The prognosis of MiNEN and pure NEC alone is different, and the selection of treatment options needs to be differentiated.

Neuroendocrine carcinoma (NEC) is a malignant tumour that originates from peptidergic neurons and neuroendocrine cells and expresses neuroendocrine markers. NEC can occur in the whole body, especially the gastrointestinal (GI) tract, lung, pancreas, and thymus. NEC of the extrahepatic bile duct (EBNEC) is very rare, accounting for only 0.32% of NEC cases[1]. The patient in the reported case had primary large cell NEC (LCNEC) of the hepatic duct combined with distal cholangiocarcinoma (dCCA), which is even rarer. After a literature search, we believe that this is the first such case reported in the world. The common locations of EBNEC are the common hepatic duct and the distal end of the common bile duct (19.2%), the middle section of the common bile duct (17.9%), the cystic duct (16.7%), and the proximal end of the common bile duct (11.5%), and the median age of patients is 47.04 years. EBNEC is likely to occur in females, with a male to female ratio of 1.0:1.6[2]. The cause of EBNEC remains unclear. Chronic inflammation of the bile duct can lead to metaplasia of endocrine cells scattered on the bile duct epithelium, which may be the initial stage of NEC development[3].

In 1959, Davies was the first to report neuroendocrine tumours (NETs), which were then called carcinoids. In 2000, the World Health Organization (WHO) officially adopted the term NET. Studies have confirmed that the incidence of NEC is showing an upwards trend. The results of the National Epidemiological Survey in the United States showed that the annual standardized incidence of NETs increased from 1.09/100000 in 1973 to 6.98/100000 in 2012, a 6.4-fold increase in the age-adjusted incidence rate[4]. The results of the Cancer Registry of Norway showed that the prevalence of NEC increased from 7.4/100000 in 1993 to 21.56/100000 in 2021[5]. Currently, the 2019 WHO standards for digestive system tumours are used for classification and grading, and NEC is divided into LCNEC, small cell NEC and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN); the 8^th edition of the American Joint Committee on Cancer is often used for staging.

In summary, the preoperative diagnosis was cholangiocarcinoma.

After preoperative preparation, pancreaticoduodenectomy was performed. During the surgery, another exophytic tumour (approximately 0.5 cm × 0.5 cm and hard in texture) was accidentally found in the common hepatic duct, and the surrounding tissues were not infiltrated. Postoperative pathology and immunohistochemistry suggested poorly differentiated LCNEC, with a size of approximately 0.5 cm × 0.5 cm × 0.4 cm, Ki-67 (50%), synaptophysin (Syn)+, and chromogranin A (CgA)+. dCCA pathology suggested moderately differentiated adenocarcinoma (Figure 2). The size of the tumour was 1.0 cm × 1.0 cm × 0.4 cm, and it infiltrated the full thickness of the bile duct wall, with nerve invasion (+) and vascular tumour thrombus (-). No residual cancer was found in the margin, and no cancer metastasis was found in lymph nodes 8, 12, and 13. The operation, which lasted for approximately 5 h, went smoothly.

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Figure 2 Histopathologic features in neuroendocrine carcinoma of the common hepatic duct coexisting with distal cholangiocarcinoma. A: The neuroendocrine carcinoma (NEC) showed a nested organoid growth pattern [hematoxylin and eosin (HE), × 100]; B: The NEC cells were round or oval, hyperchromatic nuclei and scant cytoplasm (HE, × 400); C: Immunohistochemically, the NEC cells were positive for synaptophysin(HE, × 400); D: Immunohistochemically, the NEC cells were positive for chromogranin A (HE, × 400); E: The distal cholangiocarcinoma (dCCA) cells arranged in irregular tubular and papillary structures (HE, × 100); F: Immunohistochemically, the dCCA cells were positive for cytokeratin 19 (HE, × 400).

However, severe pancreatitis occurred after surgery (Figure 1C). The patient was discharged after 2 months of treatment. The disease course was accompanied by long-term pancreatic fistula and recurrent abdominal abscess, and adjuvant chemoradiotherapy had to be delayed. Follow-up data showed that multiple metastases in the liver 12 months after surgery, multiple metastases in the pelvis and bilateral femur, peritoneal metastasis and abdominal lymph node metastasis developed in the patient 21 months after surgery. The patient died 24 months after surgery.

The majority of extrahepatic CCA is adenocarcinoma; other types, especially NEC, are very rare[6]. A literature search in the PubMed and Web of Science databases was conducted, and articles on NEC of the intrahepatic bile duct, gallbladder, and ampulla of Vater and articles with incomplete data were excluded. A total of 48 English articles on EBNEC were obtained (Table 1)[1,7-52]. The main clinical and pathological features of MiNEN and pure NEC were briefly summarized and compared (Table 2), and the baseline characteristics of the two groups, including age, sex, tumour location, tumour size, and Ki-67, were not significantly different.

A total of 48 EBNEC cases (including this case) were included in this study, but the case reported by Edakuni et al[53] was excluded because the Ki-67 index was < 10%, below the threshold for NEC according to the latest WHO classification and grading system. The median age of the patients was 68.50 years (range 61.75-75.75), the majority of patients were men, and the male to female ratio was 2:1. Due to the lack of obvious early manifestations, the lack of clinically detectable serum markers, and the fact that most patients do not have carcinoid syndrome, EBNEC is usually not diagnosed in its early stage. Nonspecific manifestations, such as jaundice, fever, abdominal pain, and abdominal distension, may occur in the middle and late stages of EBNEC, and patients often only start to pay attention to these symptoms at this time. The main clinical manifestations of the 48 EBNEC patients included jaundice (37/48), abdominal pain (16/48), weight loss (5/48), anorexia (3/48), nausea (2/48), pruritus (2/48), fever (2/48), fatigue (1/48), vomiting (1/48), and liver dysfunction (1/48). A small number of EBNECs are nonfunctional tumours in the early stage and transition into functional tumours as the disease progresses. Therefore, dynamic observation and evaluation of clinical manifestations are helpful for diagnosis.

Using colour Doppler ultrasound, CT, MRCP, and positron emission tomography-CT to preoperatively diagnose EBNEC is still difficult, and EBNEC is especially difficult to differentiate from other CCAs; however, these techniques are helpful for determining positioning and the presence of liver invasion, lymph node and distant metastasis, etc. NEC is a malignant tumour with a strong metastatic tendency. Studies have reported that more than half of patients with GI-NEC have distant metastasis when newly diagnosed[45]. Percutaneous transhepatic cholangiography (PTC), endoscopic brushing examination and needle biopsy can be used to obtain preoperative pathological results for diagnosis, but the positivity rate is low. In this study, 2 patients were pathologically confirmed by preoperative PTC[13,23], and 8 patients were pathologically confirmed by endoscopic biopsy[1,14,35-37,42,43,46]. The diagnosis of NEC often relies on immunohistochemistry, and there are a specific set of markers, such as neuron-specific enolase, CgA, Syn, and Ki-67, and cluster of differentiation 5.

Due to the low incidence, effective treatment guidelines for EBNEC are lacking, and radical surgical resection is considered the preferred treatment. In this study, 43 of 48 patients underwent surgery. The surgical method was determined based on the location of the tumour: Extrahepatic CCA resection was chosen for NEC of the common hepatic duct and upper segment of the common bile duct, and pancreatoduodenectomy was chosen for NEC of the middle and lower segments of the common bile duct; regional lymph node dissection was also recommended. For patients with focal liver metastasis, partial hepatectomy can be used to remove primary and metastatic lesions as much as possible; this approach was used in 7 of 48 patients in this study. To date, adjuvant therapy for EBNEC lacks standardization, and the roles of chemotherapy, radiotherapy and immunotherapy are still unclear. Commonly used chemotherapy regimens include cisplatin and etoposide[17,22,26,38,44] and cisplatin and irinotecan[37,39,50]. As neoadjuvant chemotherapy regimens, these two regimens can successfully achieve conversion. In this study, 4 patients received subsequent surgical treatment and achieved an overall survival (OS) of 16-23 months[13,14,23,37]. For NEC recurrence or metastasis, radiotherapy, transarterial chemoembolization, and ablation therapy should be considered. Studies have found that the expression of programmed death-ligand 1 in poorly differentiated NET cells is higher than that in well-differentiated NET cells, indicating that when applying the most appropriate settings, combinations and treatment sequences, immunotherapy may become a powerful treatment for NEC in the future[54].

EBNEC is poorly differentiated and invasive and has a poor prognosis. A recent retrospective study using the Surveillance, Epidemiology, and End Results database to perform propensity score matching of 62 EBNEC and 3215 CCA patients showed that the overall prognosis of EBNEC was better than that of CCA and that neuroendocrine components could be used as a favourable prognostic factor for CCA patients. Kaplan-Meier analysis of 45 EBNEC patients with survival follow-up data showed that the median OS was 12 months (Figure 3A); the survival of MiNEN patients was worse than that of patients with pure NEC; and the median survival of patients with MiNEN and pure NEC was 12 months and 17 months, respectively (Figure 3B), but the difference was not statistically significant (P = 0.20). We believe that the confounding non-NEC components of MiMEN may be more malignant than those of ENC, which may explain the poorer prognosis of MiMEN than pure NEC.

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Figure 3 Kaplan-Meier survival curve of the 45 neuroendocrine carcinomas of the extrahepatic bile duct patients with survival follow-up data. A: The median overall survival was 12 months; B: Kaplan-Meier survival curves of extrahepatic bile duct patients with neuroendocrine-non-neuroendocrine neoplasm and pure neuroendocrine carcinoma were compared and log-rank test were assessed for significance (P = 0.20). MiNEN: Mixed neuroendocrine-non-neuroendocrine neoplasm; EBNEC: Extrahepatic bile duct patients with neuroendocrine-non-neuroendocrine neoplasm; NEC: Neuroendocrine carcinoma.

The OS of the patient in this study was 24 months, and the prognosis was relatively good, which may be related to the early stage and low Ki-67 index of NEC and the early stage and moderate differentiation of the coexisting dCCA. To explore genetic causes, gene sequencing was performed on two types of cancer tissue, primary LCNEC of the hepatic duct and dCCA. High-throughput sequencing was performed using the Illumina NextSeq 500/550 next-generation sequencing platform and the NGS-Panel 639 developed by high-efficiency hybridization capture technology (AllNGSTM) independently developed by Yunying Medical Inspection Institute. The sequencing results are shown in Table 3. A total of 35 gene mutations were detected in NEC tissue, and 7 gene mutations were detected in adenocarcinoma tissue; additionally, the number of gene mutations in NEC was significantly higher than that in adenocarcinomas. In addition, the types and loads of gene mutations in these two types of tumours were also quite different. We speculate that different gene mutations and different loads could affect the targeted drugs and the prognosis of tumours, but the specific mechanism of action still needs to be elucidated.

This study has limitations. The main limitation is the small number of reported cases. Therefore, in future clinical work, a multidisciplinary team is needed to summarize more case reports, carry out multimodal treatment and pathogenesis studies, and establish more standardized and unified guidelines and consensus to prolong the life of EBNEC patients.

Herein, we reported a rare case of primary LCNEC of the hepatic duct combined with dCCA. The number of gene mutations in primary LCNEC of the hepatic duct in this patient was significantly greater than that in dCCA. EBNEC is very rare and invasive, making preoperative diagnosis difficult; treatment options are not uniform, and the prognosis is poor. We believe that the prognoses of MiMEN and pure NEC are different and, thus, that the selection of treatment options needs to be differentiated.