Neuroendocrine carcinoma of the common hepatic duct coexisting with distal cholangiocarcinoma: A case report and review of literature

Abstract

BACKGROUND

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.

CASE SUMMARY

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.

CONCLUSION

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

Core Tip: We reported a rare case of primary large cell neuroendocrine carcinoma (NEC) of the hepatic duct combined with distal cholangiocarcinoma (dCCA). The overall survival 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 the two types of cancer tissue. A total of 35 gene mutations were detected in NEC tissue, and 7 gene mutations were detected in adenocarcinoma tissue.

INTRODUCTION

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.

CASE PRESENTATION

Chief complaints

A 62-year-old female presented to the hospital due to recurrent abdominal pain for 2 months.

History of present illness

The pain location was identified as the middle upper quadrant. She reported that the pain was a feeling of swelling and did not radiate. She denied nausea, vomiting, chills, fever or jaundice. She had no previous history of hepatitis, tuberculosis, or special drug use, and she had no family history of cancer.

History of past illness

She was healthy and had no previous history of hepatitis, tuberculosi.

Personal and family history

She had no previous history of special drug use, and she had no family history of cancer.

Physical examination

Specialist examination at admission showed stable vital signs, no swollen superficial lymph nodes throughout the body, no yellow staining of skin and sclera, flat and soft abdomen, mild tenderness in the middle and upper abdomen, no rebound tenderness, no muscle guarding, positive Courvoisier sign, negative percussion pain in the liver and kidney region, nonpalpable liver and spleen under the ribs, negative movement dullness, and bowel sounds at 4 times/min.

Laboratory examinations

The results of a liver function examination at another hospital were as follows: Alanine aminotransferase, 174 U/L; aspartate aminotransferase, 125 U/L; alkaline phosphatase, 195 U/L; and gamma-glutamyl transferase 1036 U/L. Regarding tumour indicators, carbohydrate antigen 199 was 151.50 U/mL, and carcinoembryonic antigen and alpha-fetoprotein were normal.

Imaging examinations

Total abdominal computed tomography (CT) showed slight dilatation of the intrahepatic bile duct; the gallbladder was full in shape, with no obvious abnormal shadows. Magnetic resonance cholangiopancreatography (MRCP) showed local discontinuity of the middle segment of the common bile duct, mild dilatation of the upper segment of the common bile duct and intrahepatic bile duct, and a full gallbladder (Figure 1A). Enhanced magnetic resonance imaging of the upper abdomen showed slight thickening of the local wall of the middle and lower segments of the common bile duct with mild dilatation of the upper segment of the common bile duct and intrahepatic bile duct and an enlarged gallbladder. After admission, the IgG4 test was negative. Endoscopic ultrasound (EUS) showed a hypoechoic mass in the middle and lower segments of the common bile duct, with a size of approximately 1.02 cm × 0.9 cm and an irregular boundary (Figure 1B). EUS-guided fine needle aspiration was not performed due to the small mass.

Figure 1.

Imaging findings. A: Magnetic resonance cholangiopancreatography showed severe stenosis at the mid-portion of bile duct; B: Endoscopic ultrasound found a hypoechoic mass in the mid-portion and inferior portion of the common bile duct (white arrows); C: Computed tomography 3 d after surgery revealed significant pancreatic necrosis and exudation.

FINAL DIAGNOSIS

In summary, the preoperative diagnosis was cholangiocarcinoma.

TREATMENT

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.

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).

OUTCOME AND FOLLOW-UP

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.

DISCUSSION

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.

Table 1.

Neuroendocrine carcinoma of the extrahepatic bile duct, review of the literature

Ref.	Age	Sex	Location	Symptom	Pathology	Size (mm)	Ki-67 index (%)	Treatment	Metastasis	Prognosis
van der Wal et al[7], 1990	55	Male	Bm	Jaundice, abdominal pain	SCNEC + AC	40	NA	SR	NA	12 months, alive
Nishihara et al[8], 1993	64	Male	Bh-Bs	Jaundice, weight loss	SCNEC + AC	19	NA	SR	NA	8 months, alive
Oikawa et al[9], 1998	70	Male	Bh-Bs	Jaundice	NEC	25	NA	SR	Liver	6 months, dead
Yamamoto et al[10], 1998	71	Female	Bh	Jaundice, fever	SCNEC + AC	60	NA	SR	Liver, bone	7 months, dead
Kim et al[11], 2000	64	Male	Bm	Abdominal pain	SCNEC + AC	30	NA	SR	NA	1 months, alive
Kuraoka et al[12], 2003	75	Male	Bi	Jaundice	SCNEC	45	90	SR	LN	5 months, alive
Hazama et al[13], 2003	60	Male	Bi	Jaundice	SCNEC	3	NA	SR	Brain, LN	17 months, dead
Park et al[14], 2004	60	Female	Bs-Bm	Jaundice	SCNEC	30	NA	SR	Brain, LN	17 months, dead
Thomas et al[15], 2005	54	Male	Bh-Bm	Jaundice	SCNEC	NA	NA	SR	Brain	6 months, alive
Kaiho et al[16], 2005	66	Female	Bi	Abdominal pain	SCNEC + AC	35	NA	SR + chemo	Liver	8 months, dead
Viana Miguel et al[17], 2006	76	Male	Bm	Jaundice	SCNEC	NA	NA	SR + chemo + radio	NA	5 months, alive
Jeon et al[18], 2006	65	Male	Bs-Bm	Jaundice	SCNEC	20	NA	SR + chemo	Liver	12 months, dead
Sato et al[19], 2006	68	Male	Bi	Jaundice	LCNEC + AC	20	71.4	SR	Liver	3 months, dead
Nakai et al[20], 2008	32	Male	Bs-Bi	Abdominal pain	SCNEC	NA	NA	NA	Liver, lung	18 d, dead
Hosonuma et al[21], 2008	69	Female	Bh-Bs	Jaundice	SCNEC	30	NA	NA	NA	2 months, dead
Arakura et al[22], 2008	75	Male	Bh-Bm	Jaundice	SCNEC	65	NA	Chemo + radio	Peritoneal, pleural, LN	10 months, dead
Okamura et al[23], 2009	62	Male	Bm	Abdominal, pain, fever	SCNEC	30	NA	SR + chemo + radio	Bone, LN	23 months, dead
Kohashi et al[24], 2009	77	Male	Bi	Jaundice	LCNEC	18	67	SR	Liver, lung, local	3 months, dead
Cho et al[25], 2009	59	Female	Bh	Jaundice, abdominal pain	SCNEC	30	NA	SR	NA	6 months, alive
Demoreuil et al[26], 2009	73	Male	Bs	Jaundice, abdominal pain, weight loss	LCNEC + AC	30	50	SR + chemo	Lung, peritoneal	12 months, dead
Masui et al[27], 2011	82	Male	Bm	Jaundice, anorexia	MANEC	25	35	SR	Liver	6 months, dead
Takahashi et al[28], 2012	28	Female	Bm	Pruritus	NEC	30	89.8	SR	None	36 months, alive
Ninomiya et al[29], 2013	74	Female	Bm	Jaundice	SCNEC	30	NA	SR	NA	14 months, alive
Sasatomi et al[30], 2013	76	Male	Bh	Jaundice	LCNEC	50	75	SR	LN	21 d, dead
Linder et al[31], 2013	82	Male	Bi	Jaundice, abdominal pain, weight loss	MANEC	19	NA	SR	None	6 months, alive
Park et al[32], 2014	75	Female	Bm	Nausea, jaundice	LCNEC	27	NA	SR + chemo	Local	12 months, dead
Lee et al[33], 2014	75	Male	Bs	Jaundice	SCNEC + AC	20	NA	SR	None	11 months, alive
Wysocki et al[34], 2014	65	Male	Bm	Jaundice, vomit, weight loss	LCNEC + AC	36	80	SR	NA	5 months, dead
Aigner et al[35], 2015	61	Male	Bm	Abdominal pain, jaundice, nausea, pruritus	SCNEC	27	90	SR + chemo	Liver, LN, bone	3 months, alive
Kihara et al[36], 2015	70	Female	Bh	Jaundice	SCNEC	30	70	SR + chemo	None	10 months, alive
Nakamaru et al[37], 2015	75	Male	Bh-Bm	Jaundice	SCNEC	40	NA	SR + chemo	NA	16 months, alive
Oshiro et al[38], 2016	72	Male	Bs	Jaundice	LCNEC	30	56.2	SR + chemo	Liver	7 months, alive
Katada et al[39], 2016	78	Male	Bh	Jaundice	SCNEC	30	NA	SR + chemo	NA	5 months, alive
Murakami et al[40], 2016	80	Male	Bm	Jaundice, anorexia	LCNEC + AC	24	72	SR	Liver, lung, peritoneal	3 months, dead
Priyanka Akhilesh et al[41], 2016	76	Male	Bh	Jaundice, weight loss	MANEC	14	90	SR	NA	NA
Izumo et al[42], 2017	66	Male	Bi	Jaundice, anorexia, fatigue	LCNEC + AC	10	30	SR	None	30 months, alive
Komo et al[43], 2017	82	Male	Bi	Liver dysfunction	MANEC	18	37	SR	None	7 months, alive
Park and Jeon[44], 2018	59	Male	Bh	Jaundice	LCNEC	62	20	SR + chemo	None	10 months, alive
Zhang et al[45], 2018	62	Male	Bh	Jaundice	SCNEC	20	80	SR	Liver	6 months, dead
Koo et al[46], 2019	77	Female	Bh	Jaundice, abdominal pain	LCNEC	10	60	Radio	Liver	1.5 months, alive
Zhang et al[47], 2019	60	Male	Bh-Bs	Abdominal pain	LCNEC + AC	17	70	SR	NA	NA
Zhang et al[48], 2019	64	Female	Bi	Jaundice, abdominal pain	MANEC	45	50	SR	Liver, lung	12 months, dead
Kamiya et al[49], 2020	84	Male	Bm	Jaundice, abdominal pain	MANEC	25	80	SR	Liver	3 months, dead
Kiya et al[50], 2021	29	Female	Bm	Abdominal pain	LCNEC	50	90	SR + chemo	NA	16 months, alive
Sugita et al[51], 2022	62	Female	Bi	Jaundice	SCNEC + AC	19	80	SR	NA	4 months, alive
Han et al[52], 2023	84	Female	Bs	Abdominal pain	SCNEC	17	85	NA	NA	NA
Jevdokimov et al[1], 2023	42	Female	Bs	Jaundice	NEC	30	75	SR + chemo	NA	4 months, alive
This study	62	Female	Bh	Abdominal pain	LCNEC	5	50	SR	Liver, LN, bone	24 months, dead

AC: Adenocarcinoma; NEC: Neuroendocrine carcinoma; SCNEC: Small cell neuroendocrine carcinoma; LCNEC: Large cell neuroendocrine carcinoma; MANEC: Mixed adenoneuroendocrine carcinoma; SR: Surgical resection; Chemo: Chemotherapy; Radio: Radiotherapy; Bh: Hilar bile duct; Bs: Superior portion of common bile duct; Bm: Mid-portion of common bile duct; Bi: Inferior portion of common bile duct; LN: lymph node(s); NA: not available.

Table 2.

Comparison of neuroendocrine-non-neuroendocrine neoplasm and pure neuroendocrine carcinoma in the extrahepatic biliary tract

	MiNEN	Pure NEC
Number of cases	19	29
Age, yr	70.47 ± 8.67	64.07 ± 14.88
Sex
Male	15	17
Female	4	12
Location
CHD	2	8
CBD	15	5
CHD + CBD	2	16
Symptom
Jaundice/pruritus	15	24
Abdominal pain	8	8
Anorexia/nauseas/vomit/fatigue/weight loss/ fever	9	3
Size, mm	26.63 ± 12.22	30.15 ± 15.08
Ki-67 index, %	62.12 ± 20.61	69.42 ± 20.75
Treatment
SR	17	12
SR + chemo/radio	2	12
Chemo/radio	0	2
Metastasis
Liver	7	9
Lymph node	0	8
Lung	3	2
Bone	1	3
Brain	0	3
Peritoneal/pleural/local	2	3

MiNEN: Mixed neuroendocrine-non-neuroendocrine neoplasm; NEC: Neuroendocrine carcinoma; CHD: Common hepatic duct; CBD: Common bile duct; SR: Surgical resection; Chemo: Chemotherapy; Radio: Radiotherapy.

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.

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.

Table 3.

Comparison of gene mutations in the two primary bile duct tumours

Gene	LCNEC	dCCA
ERBB2	14.10%, exon17, c.2033G>A, p.R678Q	3.70%, exon17, c.2033G>A, p.R678Q
	10.80%, exon17, c.1970C>T, p.A657V
ERBB3	20.10%, exon3, c.310G>A, p.V104M	3.60%, exon3, c.310G>A, p.V104M
LCE1F	43.40%, exon2, c.244C>T, p.R82W	41.70%, exon2, c.244C>T, p.R82W
MSH6	47.80%, exon5, c.3173-3C>G	47.30%, exon5, c.3173-3C>G
	18.00%, exon6, c.3514dup, p.R1172fs
FCAMR	47.00%, exon4, c.250C>T, p.R84W	47.90%, exon4, c.250C>T, p.R84W
BRAF	No	1.30%, exon11, c.1391G>T, p.G464V
CREBBP	45.10%, exon28, c.4711G>A, p.A1571T	52.90%, exon28, c.4711G>A, p.A1571T
ARID1A	17.20%, exon5, c.2077C>T, p.R693*	No
	17.20%, exon20, c.5842_5843del, p.S 1948fs
KMT2C	13.30%, exon46, c.11878C>T, p.R3960	No
	19.80%, exon36, c.5668C>T, p.R1890
KMT2D	21.30%, exon12, c.3318del, p.S1107fs	No
KRAS	18.50%, exon2, c.38G>A, p.G13D	No
CDKN2A	22.20%, exon2, c.238C>T, p.R80	No
ATR	19.30%, exon7, c.1544G>A, p.R515H	No
NTRK1	15.30%, exon11, c.1330C>T, p.R444W	No
CDC73	12.40%, exon6, c.439C>T, p.R147C	No
FOXP1	29.40%, exon12, c.952G>A, p.E318K	No
FBXW7	30.10%, exon10, c.1514G>A, p.R505H	No
MAP3K1	25.10%, exon3, c.746G>A, p.R249H	No
CTNNA1	13.50%, exon7, c.943G>A, p.G315R	No
PRKDC	15.30%, exon73, c.10241C>T, p.T3414M	No
RUNX1T1	23.10%, exon8, c.1084G>A, p.A362T	No
RIC8A	21.30%, exon3, c.568C>T, p.R190C	No
CBL	8.90%, exon14, c.2222C>T, p.A741V	No
KDM5A	15.60%, exon26, c.4400G>A, p.R1467Q	No
	19.80%, exon23, c.3470G>A, p.R1157H
RB1	15.10%, exon8, c.763C>T, p.R255*	No
	15.30%, exon18, c.1735C>T, p.R579*
TP53	2.20%, exon5, c.473G>A, p.R158H	No
BCOR	15.10%, exon4, c.1754G>T, p.R585M	No
STAG2	19.60%, exon9, c.775C>T, p.R259*	No
BCORL1	21.80%, exon4, c.1279G>A, p.A427T	No
	18.10%, exon8, c.4258C>T, p.R1420*

LCNEC: Large cell neuroendocrine carcinoma; dCCA: Distal cholangiocarcinoma.

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.

CONCLUSION

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.