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21 June 2023: Articles  Latvia

Neuroendocrine Carcinoma of the Extrahepatic Bile Ducts: A Case Report

Challenging differential diagnosis, Rare disease

Denis Jevdokimov ORCID logo1ABCDEFG*, Elina Tauvena2BDF, Natalija Jevdokimova3ACDEF, Sofija Vilisova4BF, Olga Kriviča5B, Inese Briede ORCID logo67BDF, Tatjana Tone67DEF, Aiga Staka1ACDEF, Aija Gerina-Berzina4CDF, Arturs Ozolins28CDE, Aldis Pukitis1ACDEF

DOI: 10.12659/AJCR.939239

Am J Case Rep 2023; 24:e939239




BACKGROUND: Neuroendocrine tumors (NETs) primarily originating from the extrahepatic biliary (EB) tree are a medical rarity, accounting for less than 100 recorded instances globally. This case report outlines an encounter with this uncommon condition, demonstrating the complexities of diagnosis and management.

CASE REPORT: A 42-year-old woman presented at our Emergency Department with a 3-week history of itching and symptoms of obstructive jaundice. Initial laboratory tests showed hyperbilirubinemia and elevated liver transaminases. Abdominal ultrasonography indicated choledocholithiasis. Magnetic resonance imaging suggested either Mirizzi syndrome or a proximal common bile duct neoplasm. Abdominal computed tomography showed cholestasis, suggesting choledocholithiasis or cholangiocarcinoma (type-1). An endoscopic retrograde cholangiopancreatography with biliary and pancreatic duct stenting was performed for drainage, with brush cytology confirming adenocarcinoma. The patient was referred for surgical resection of the bile duct tumor, involving extrahepatic bile duct resection, en bloc cholecystectomy, lymphadenectomy, Roux-en-Y anastomosis, and biliary drainage. Histopathology identified a neuroendocrine carcinoma. Following surgery, the patient underwent eight cycles of FOLFOX6 chemotherapy, with no disease relapse post-treatment.

CONCLUSIONS: This case emphasizes multidisciplinary teamwork importance in managing rare diseases like EB bile duct NETs. These tumors' rarity and symptom ambiguity necessitate histological examination for accurate diagnosis. This report aims to guide healthcare professionals facing similar future cases.

Keywords: case reports, Pruritus, Cholangiopancreatography, Endoscopic Retrograde


Neuroendocrine tumors (NETs) are rare tumors that are derived from peptidergic neurons and neuroendocrine cells. NETs can be seen in multiple organs throughout the body, including the digestive tract, lungs, thymus, and uterus. NETs most often occur in the gastrointestinal tract and pancreatic tissue and are extremely rare in the common bile duct [1]. The presenting signs and symptoms of extrahepatic NETs are those of mechanical cholestasis due to the obstruction of the bile ducts [2]. Herein, we present the case of biliary stricture caused by biliary neuroendocrine carcinoma. A diagnosis is rarely made during preoperative examinations, and a definitive diagnosis is established intraoperatively or after histopathological evaluation [3].

Case Report


A 42-year-old woman presented to the Emergency Department of our hospital with concerns of itching, painless jaundice, pale stool, dark urine, and occasional vomiting. The patient’s symptoms began 3 weeks before admission to the hospital. The patient had no previous medical history. The vital signs were as follows: heart rate, 83 beats per min; respiratory rate, 16 breaths per min; blood pressure, 134/80 mmHg; and oxygen saturation in ambient air, 98%. The patient’s temperature was 36.9°C. The skin and sclera were icteric. Abdominal examination was without tenderness, pain, or palpable masses. Blood analysis revealed normal leukocyte, hemoglobin, and thrombocyte levels. The bilirubin level was increased, at 60 μmol/L, and alkaline phosphatase, at 363 U/L. The alanine amino transferase level was increased, at 1064 U/L, and aspartate amino transferase, at 599 U/L. The coagulation tests and urinalysis were within the reference range. Gastrointestinal tumor markers (cancer antigen [CA] 19-9, carcinoembryonic antigen [CEA]) were within the reference range. Based on an outpatient abdominal ultrasonography, choledocholithiasis was suspected. Based on an abdominal magnetic resonance scan, Mirizzi syndrome or biliary neoplasm was suspected (Figure 1). An initial radiological diagnostic workup at the hospital was scheduled. An abdominal computed tomography (CT) scan revealed a 2.5-cm-long contrast-accumulating tissue mass involving and obstructing the common bile duct from 1 cm below the confluence and reaching the intrapancreatic part of the common bile duct.

The patient was further evaluated by endoscopic retrograde cholangiopancreatography to ensure bile drainage and brush cytology. Wire-guided cannulation and radiological visualization of the common bile duct’s distal part was without any pathology; however, in the proximal part, a 25-mm-long stricture with dilated intrahepatic ducts above (Figure 2) was visualized. During endoscopic retrograde cholangiopancreatography, insertion of the pancreatic duct with a 5-cm stent and common bile duct with 9-cm 8.5 French plastic stent (Advanix™ Boston Scientific) was performed. The brush cytology from stricture confirmed ductal adenocarcinoma. A multidisciplinary consilium referred the patient to surgical resection of the bile duct tumor.


Based on the diagnostic workup, a diagnosis of common bile duct tumor was made. The patient underwent a bile duct re-section with cholecystectomy and the additional dissection of lymph nodes along the common bile duct, hepatic artery, and portal vein. Proximal and distal bile duct frozen section biopsy showed tumor-free margins. Hepaticojejunal Roux-en-Y anastomosis was conducted. The surgery duration was 5 h. The postoperative course was uneventful, and the patient was discharged without any postoperative complications.

The gross description of the surgical specimen was as follows: the gallbladder was 10×4×1 cm with bile duct fragments of 3×4×1 cm, and the lumen of the ductus choledochus was filled with a local solitary yellowish mass of 3×2×2 cm spreading into the ductus cysticus (Figure 3).

Postoperative histologic examination (Figure 4) revealed bile duct neuroendocrine carcinoma PT1N0M0G3R0. Microscopically, tumor cells were highly pleomorphic, with nuclear atypia, hyperchromasia, and a high mitotic figure number (92 mitoses per 50 high-powered field). Immunohistochemical analysis showed expression of keratin (AE1/AE3) and synaptophysin, while chromogranin was equivocal and CD56 was negative (Figure 5). The Ki-67 labeling index was 75% to 80% of cells (counted manually with a printed image). Lymph nodes were without malignant signs.

A multidisciplinary team referred the patient to adjuvant systemic treatment. The patient was treated on an outpatient basis with the FOLFOX6 regimen. A less toxic regimen was chosen due to recent hyperbilirubinemia and elevated liver function tests. The FOLFOX6 regimen consisted of a 2-h infusion of oxaliplatin (85 mg/m2), a 2-h infusion of leucovorin (400 mg/m2), and 5-fluorouracil (5-FU) infusion bolus (400 mg/m2) on day 1 followed by 5-FU 46-h infusion (2400 mg/m2) via elastomeric infusion pump. The FOLFOX6 regimen was repeated at 2-week intervals.

The patient received 8 cycles of FOLFOX6 treatment. The adverse drug event evaluation was performed at baseline and was repeated before every cycle by assessing the complete blood count and liver and kidney function tests. The CEA, CA 19-9, and chromogranin A levels were assessed at baseline. The chromogranin A level was 115 ug/L (reference range, <100 ug/L). The CEA and CA 19-9 tests were repeated every cycle and were within the reference range. After the fourth cycle, an abdominal CT and Tc-99m-tectrotyd scintigraphy were performed and were negative.


The final diagnosis of the presented case was biliary neuroendocrine carcinoma involving the common hepatic duct, common bile duct, and cystic duct, with classification PT1N0M0G3R0.


We reported a rare case of neuroendocrine carcinoma in the extrahepatic bile ducts that was originally diagnosed as adenocarcinoma by brush cytology and treated with radical re-section. Later postoperative histologic examination revealed bile duct neuroendocrine carcinoma.

World Health Organization classification categorizes neuroendocrine neoplasms of the digestive tract into 3 subtypes: well-differentiated NET, poorly differentiated neuroendocrine carcinoma, and mixed neuroendocrine-non-neuroendocrine neoplasm [4]. Neuroendocrine neoplasms can arise in various organs throughout the body. However, according to data from literature, those arising in the gastrointestinal tract and the pancreas are extremely rare, accounting for approximately 1% to 1.5% of all gastroenteropancreatic neoplasms. The annual age-adjusted incidence of gastroenteropancreatic neuroendocrine neoplasms in the United States was 3.56 per 100 000 persons in 2012, which is rare, but steadily increasing [5,6]. The most common origin from the digestive system was the small intestine, which was approximately 1.05 per 100 000 persons, then the rectum (1.04 per 100 000 persons), and only then the pancreas (0.84 per 100 000 persons). Statistical resources mentioned that 0.32% of neuroendocrine neoplasms occur in the extrahepatic bile duct, and almost all of them are well-differentiated NETs. Poorly differentiated neuroendocrine carcinomas of the extrahepatic bile duct are rare, reportedly accounting for only 0.19% of extrahepatic bile duct malignancies [5,6]. The most frequent sites of extrahepatic biliary NETs are the common hepatic duct and distal common bile duct (19.2%), followed by the middle of the common bile duct (17.9%), cystic duct (16.7%), and proximal common bile duct (11.5%) [7].

These neoplasms are different in histologic features and proliferation fractions. Well-differentiated NETs microscopically are encamped in nests, clusters, trabeculae, and acini and consist of cells with rounded nuclei, dotted chromatin, and eosinophilic to transparent cytoplasm. They are categorized into 3 groups according to activity: grade 1 (<2 mitoses/2 mm2, Ki-67 <3%), grade 2 (2–20 mitoses/2 mm2, Ki-67: 3–20%), and grade 3 (>20 mitoses/2 mm2, Ki-67 >20%). A neuroendocrine carcinoma is a high-grade malignant neuroendocrine neoplasm consisting of small, intermediate, or large cells with severe nuclear atypia and a high proliferation fraction (>20 mitoses per 10 high-power fields or >20% Ki-67 index) [8]. Mixed neuroendocrinenon-neuroendocrine neoplasms can have non-endocrine components other than adenocarcinoma. Insulinoma-associated protein 1 (INSM1) is a highly specific neuroendocrine marker, which we do not use in our country. However, in the present case, when chromogranin was equivocal, INSM1 positivity would have supported the diagnosis.

NET of the common bile duct in most cases is presented as jaundice and fever. NET has the potential to secrete numerous hormonal substances, but usually named substances are not measured through preoperative diagnosis.

We would like to emphasize that this case presents a young female with painless jaundice and other typical symptoms of obstructive jaundice that are often mentioned in the literature. It is important to distinguish neuroendocrine carcinomas from other causes of obstructive jaundice. In this situation, multidisciplinary teamwork and performing radiological, endoscopic, surgical, and histopathological methods can help to reach the correct final diagnosis. Experience, knowledge, and use of new diagnostic and treatment methods in a multidisciplinary team will improve care, detection, and treatment outcome of this disease. Many cases of bile duct NET are diagnosed after surgery and histopathological examination [9]. Surgical resection is the main treatment for NET and surgical extent is directed by the tumor location. Based on the treatment paradigm for a local disease of small-cell lung cancer, a course of chemotherapy can be considered in many patients with loco-regional poorly differentiated neuroendocrine carcinomas due to the aggressive behavior of these neoplasms. Poorly differentiated neuroendocrine carcinomas have common histological similarities with small-cell carcinoma of the lung. Poorly differentiated neuroendocrine carcinomas are characterized by a high mitotic rate, extensive necrosis, and high proclivity for metastatic dissemination [10].

Common regimens for biliary neuroendocrine carcinomas consist of cisplatin and etoposide. Cisplatin or carboplatin and etoposide are recommended by the European Neuroendocrine Tumor Society as a therapeutic algorithm for gastroenteropancreatic neuroendocrine carcinomas, and irinotecan- or oxaliplatin-based regimens can be considered as second-line therapy. Clinical judgement should be used since the role of adjuvant systemic treatment in biliary neuroendocrine carcinomas remains indefinite [11].

Neoadjuvant chemotherapy in some cases can be a better choice than adjuvant chemotherapy. Occult metastases can already occur in many patients with neuroendocrine carcinoma at the time of diagnosis, resulting in early recurrence and disease progression after surgical treatment. Neoadjuvant chemotherapy with a platinum-based regimen can deal with occult metastases because the tumor is relatively sensitive. Moreover, before surgical treatment, the chemotherapy can improve the quality of life, which allows for more aggressive treatment to be administered. From this perspective, neoadjuvant treatment might be preferred to adjuvant treatment for patients with extrahepatic bile duct neuroendocrine carcinoma, even in cases in which it can be surgically removed.

Immunotherapy has the potential to be a powerful treatment option in the future for neuroendocrine carcinomas when the most appropriate setting, combination, and treatment sequence are found. Poorly differentiated neuroendocrine neoplasms have higher expression of PD-L1 on tumor cells than do well-differentiated neuroendocrine neoplasms. As chemotherapy has the ability to increase tumor mutational burden, immunotherapy after chemotherapy could improve immune checkpoint inhibition efficacy [12]. Laboratory findings of biliary neuroendocrine carcinomas usually show elevated CEA and CA 19-9, which are classic but nonspecific biomarkers. Serum hormone levels in bile duct neuroendocrine neoplasms are usually in reference range limits corresponding to bile duct neuroendocrine carcinomas being functionally indolent, in contrast to other types of neuroendocrine carcinomas, such as pancreatic neuroendocrine carcinomas [13]. Assessing the natural history of this disease, malignant potential, and prognosis of the tumors is difficult because of the rarity and lack of long-term follow-up data. For a better assessment, continued detailed reporting of such cases is crucial. By gaining and sharing experience, uniform guidelines for the treatment of neuroendocrine carcinoma of the common bile duct could be established.


Due to the rarity of extrahepatic bile duct neuroendocrine carcinoma, preoperative diagnosis is challenging, as typical carcinoid flushing symptoms are usually absent; therefore, histological examination is of the utmost importance for a definitive diagnosis. A combination of early radical surgery and adjuvant chemotherapy provides significant improvement in prognosis. This case highlights the ultimate importance of multidisciplinary teamwork and performing noninvasive and invasive methods for reaching a final diagnosis.


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2.. Khan FA, Stevens-Chase A, Chaudhry R, Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct: Int J Surg Case Rep, 2017; 30; 46-49

3.. Abe T, Nirei A, Suzuki N, Neuroendocrine tumor of the extrahepatic bile duct: A case report: Int J Surg Case Rep, 2017; 40; 6-9

4.. Miri SR, Movaghar ER, Safaei M, Sharifi A, Neuroendocrine tumor of the common bile duct: A case report of extremely rare cause for obstructive jaundice: Int J Surg Case Rep, 2020; 77; 303-6

5.. Fernández-Ferreira R, Medina-Ceballos E, Soberanis-Piña PD, Neuroendocrine tumor of the common bile duct: Case report: Case Rep Oncol, 2021; 14(3); 1785-91

6.. Kamiya M, Yamamoto N, Kamioka Y, Rapidly progressed neuroendocrine carcinoma in the extrahepatic bile duct: A case report and review of the literature: Surg Case Rep, 2020; 6(1); 191

7.. Raspanti C, Falco N, Silvestri V, Neuroendocrine tumor of the common bile duct: Case report: G Chir, 2016; 37(6); 275-80

8.. Klimstra DS, Modlin IR, Coppola D, The pathologic classification of neuroendocrine tumors: A review of nomenclature, grading, and staging systems: Pancreas, 2010; 39(6); 707-12

9.. Hoepfner L, White JA, Primary extrahepatic bile duct neuroendocrine tu-mor with obstructive jaundice masquerading as a Klatskin tumor.: J Surg Case Rep., 2017; 2017(6) rjx104

10.. Strosberg JR, Coppola D, Klimstra DS, The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas: Pancreas, 2010; 39(6); 799-800

11.. Garcia-Carbonero R, Sorbye H, Baudin E, ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas: Neuroendocrinology, 2016; 103(2); 186-94

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923