A 17-year-old boy presented to our hospital with jaundice and pruritus lasting 1 week. Physical examination revealed no other abnormalities. Laboratory tests indicated obstructive jaundice. Liver biochemistry data revealed the following: total bilirubin, 276.1 µmol/L; direct bilirubin, 187.5 µmol/L; alanine aminotransferase, 211 U/L; aspartate aminotransferase, 222 U/L; alkaline phosphatase, 617.5 U/L; gamma-glutamyl transpeptidase, 117.2 U/L; cancer antigen 19–9 (CA 19–9), 92.4 U/mL. No significant abnormalities were observed for the other tumor markers. Tests for hepatitis B virus surface antigen, hepatitis B virus surface antibody, hepatitis B virus e antigen, and hepatitis C virus antibody were negative. A contrast-enhanced abdominal computed tomography scan revealed the hilar bile duct to be locally enhanced, with nodule-like thickening and luminal narrowing(Fig. 1a), significant stenosis was not observed at either the left or right hepatic duct openings, and the intrahepatic bile ducts above were visibly dilated, without enlargement of the gallbladder or any readily visible nodules in the liver(Fig. 1b), considering bile duct cancer in the hilar bile duct . Computed tomography angiography showed that the origin and direction of extension of the common hepatic artery and its branches were normal, with no readily visible stenosis or dilatation. The main trunk of the portal vein was not widened, and there were no obvious filling defects in it. The opening and course of the left, middle, and right hepatic veins were normal, with no obvious signs of stenosis or dilatation(Fig. 1c) .
Preoperatively, the boy was diagnosed with a malignant tumor of the hilar bile duct (Bismuth-Corlette II was considered) without metastasis to other organs or tissues. After the evaluation of multidisciplinary discussion, he underwent resection of the common bile duct and common hepatic duct with gallbladder and Roux-en-Y hepaticojejunostomy. Intraoperatively, we found that the tumor was located at the bifurcation of right and left hepatic ducts, and it was approximately 1.2 cm in diameter. Extrahepatic bile duct resection from the hepatic hilar to the pancreas together with cholecystectomy and lymphadenectomy resection were performed (Fig. 2a). The left and right hepatic duct margins were sent for intraoperative frozen pathology examination, and a small number of moderate to severe atypical dysplastic cells were visible in the right hepatic canal margins (Fig. 3a). For this reason, we removed 0.5 cm right liver tube, and the freezing results showed no abnormality. Then, the right anterior and right posterior branches and the left hepatic bile were integrated into a larger bile duct opening, and Roux-en-Y hepaticojejunostomy was performed with the jejunum approximately 15 cm downstream of the ligament of Treitz (Fig. 2b). Histologic examination showed low differentiation of the neuroendocrine tumor (NET) of the hilar bile duct (G3) (Fig. 3b). The tumor infiltrates the bile duct wall and involves the surrounding fibrous adipose tissue. We tested 19 lymph nodes, all of which were negative. Immunohistochemistry indicated that CD31 (intravascular tumor plugs were detected), CD56(+), CEA(−), CK19(+), D2-40 (no tumor plugs were detected in the lymphatic vessels), Desmin(−), Ki67(20%), S100 (nerve invasion were be detected), Syn(+), and CgA(−). Postoperative recovery was regular. The patient was placed on a fluid diet on the 3rd postoperative day. No complications were observed, and the patient was discharged on the 8th postoperative day.
NETs are unique tumors with typical histological, clinical, and biological characteristics. They include multipotent cells that can secrete large amounts of hormonal substances and vasoactive peptides. These include gastrin, somatostatin, vasoactive intestinal peptide, insulin, and glucagon [3,4]. However, extrahepatic biliary NETs rarely secrete hormonal substances or vasoactive peptides that cause the corresponding clinical symptoms. NETs are caused by Kulchitsky cells in the Lieberkuhn crypt, which are visible in the gastrointestinal tract but very rare in the biliary system, which explains the low incidence of NETs of the extrahepatic bile duct.
Because extrahepatic biliary NETs are rare and there is a lack of large case studies reported, Michalopoulos et al. performed a retrospective study in which they reported approximately 38 cases of extrahepatic biliary NETs from 1961 to 2013 in patients with a median age of 47 years (range 6–79 years) and a female predominance (61.5%) . To date, only 8 cases in adolescents have also been reported. The youngest of these cases was reported by a Mexican scholar, a case of a 12-year-old girl diagnosed with an extrahepatic biliary NET. She underwent resection of the common bile duct, cholecystectomy and end to side Roux-en-y hepaticojejunostomy, and portal lymphadenectomy . NETs of the extrahepatic bile ducts can produce clinical symptoms, but these symptoms are usually related to obstruction of the bile ducts due to the increasing size of the tumor and compression of the surrounding tissues. They are rarely due to hormones or vasoactive intestinal peptides secreted. The most common clinical symptoms of NETs of extrahepatic bile are jaundice (60.3%) and pruritus (19.2%). Hormone and vasoactive peptide-associated symptoms were only reported in 9% of cases .
It has been reported that NETs of the extrahepatic biliary occur in the hilar bile duct (11.5%), common bile duct (17.9%), cystic duct (16.7%), and distal common bile duct (19.2%), and the surgical approach to tumors at different sites varies . In general, the surgical procedure for NETs of extrahepatic biliary is basically the same as that for adenocarcinoma of extrahepatic bile duct. In our case, the tumor was located at the bifurcation of right and left hepatic ducts, and postoperative pathological examination showed that the tumor had infiltrated the bile duct wall and involved the surrounding adipose tissue. Fortunately, we performed complete resection of the tumor and resection of the surrounding fibrous adipose tissue and lymphatic tissues, which theoretically achieved a good curative effect. The imaging presentation of NETs of extrahepatic biliary is similar to that of cholangiocarcinoma, and accurate preoperative diagnosis is difficult due to the lack of detectable serum markers and clinical hormone-related symptoms in patients. One study showed that only 4 of 87 patients were diagnosed with neuroendocrine or extrahepatic biliary tumors before surgery, and 2 of them had significantly elevated serum 5-hydroxytryptamine levels. In the other two patients, intraoperative biopsies were performed for pathological diagnosis during endoscopic retrograde cholangiopancreatography .
Currently, surgery is the most effective treatment for extrahepatic biliary NETs. Palliative treatment including systemic chemotherapy, growth inhibitor analogs, targeted therapy, and peptide receptor radionuclide therapy may also be able to control the progression of the disease to some extent, but most of these treatments are applicable to NETs of the gastroenteropancreatic system and not to extrahepatic biliary NETs . After all, NETs of the extrahepatic bile duct are rare. Only a few cases have been reported, and there is a dearth of systematic and large samples of data on the effects of clinical drug therapy.