IPNB is defined by WHO as "an exogenous papillary mass of bile duct epithelial origin, mainly growing in the bile duct lumen, which can occur in any part of the biliary tract system including the intrahepatic bile duct and the extrahepatic bile duct. Some tumors have the characteristics of secreting mucus".3
Its clinical manifestations are recurrent pain in the right costal region and acute cholangitis signs namely, intermittent jaundice and fever. These clinical manifestations may be related to acute biliary obstruction caused by the fragility of the tumor, or to transient biliary obstruction caused by the secretion of mucus from some tumors. Some patients could be asymptomatic. IPNB can appear single or multiple, benign or malignant. About 35% of IPNB patients have malignant transformation at the time of onset or during follow-up. According to its pathological characteristics, it can be divided into low-grade lesions and high-grade lesions, among which low-grade lesions are often called "papillary adenoma", and high-grade lesions are called "non-invasive papillary carcinoma."4
A neuroendocrine tumor (NET) originates from APUD cells and is common in the gastrointestinal tract and respiratory tract. NETs occurring in the biliary tract (BNET) are extremely rare, accounting for 0.2–2% of all gastrointestinal NETs.5 BNET can occur in any part of the extrahepatic bile duct, of which the hepatic duct and distal bile duct are the most common locations, followed by the middle bile duct, gallbladder duct, and proximal bile duct.6 Most of these tumors are non-functional, and a few have the function of secreting hormones or vasoactive substances like serotonin, gastrin, insulin, calcitonin, vasoactive intestinal peptide, etc. Only about 9% of them cause carcinoid syndrome.7 Clinical manifestations of BNET patients are mainly dependent on tumor size, location, invasion of adjacent tissues or distant metastasis, etc. The most common clinical manifestation of BNET patients is jaundice.8
Our patient manifested with recurrent pain and discomfort in the right upper abdomen, and jaundice. Later, the patient was treated for ascites. The patient had a viscous and colloid hemorrhagic ascites, which was consistent with IPNB characteristics. Jaundice and bile duct stones were related to the mucus secretion function, while stenosis of the lumen was caused by the tumor itself. The invasive growth and short-term distant metastasis of the tumor may be related to NET characteristics.
The most important imaging features are the communication between the lesion and the dilated bile duct and multiple nodules in the lesion. CT and magnetic resonance imaging (MRI) show that the tumors are mostly located in the dilated part of the intrahepatic bile duct, forming papillary and polyp-like accessory wall nodules, which are significantly strengthened in the early stage. Some tumor cells secrete too much mucus, resulting in bile duct dilatation, sometimes accompanied by dilation of the main pancreatic duct and expansion of the duodenal papilla.9 The gross pathological features of IPNB are single or multiple, gray or yellow, brittle papillary masses in the bile duct, or diffuse villous masses in the bile duct. Microscopically, papillary proliferation of bile duct epithelial cells manifesting as adenoma or adenocarcinoma can be seen. It is connected to the bile duct wall with a pedicle-like structure composed of a fibrous vascular matrix surrounded by the upper skin.10 In this case, a 2.5 x 4.5 x 1.5 cm mass in the lumen of the common bile duct, surrounded the wall of the duct and was accompanied by silt-like calculi, visible to the naked eye, which was consistent with the imaging findings of the disease.
NET is difficult to distinguish from other types of cholangiocarcinomas via imaging. Preoperative tumor markers such as AFP, CEA, CA l9-9, and CA 125 are non-specific, and the diagnosis mainly depends on pathology. Immunohistochemical analysis and detection items include Syn and CgA which help in determining the neuroendocrine cell characteristics of tumor cells, and the Ki-67 index which indicates the degree of tumor malignancy.11 According to the fifth edition of the WHO classification of digestive system tumors, when extrahepatic bile duct papillary tumors progress to invasive cancer, high-grade intraepithelial neoplasia is usually observed, and the invasive components are mostly tubular adenocarcinoma or small cell neuroendocrine carcinoma. In this case, postoperative imaging visualized the tumor in the lower part of the common bile duct and a polypoid growth around the circumference. Under the microscope, the tumor penetrated the common bile duct wall and invaded the adjacent tissues. Immunohistochemical results showed Syn (+), CgA (+), and Ki-67 > 80%. The infiltrating component was consistent with small cell carcinoma, suggesting a poor prognosis.
Both pure intrabiliary papillary tumors and BNETs are rare primary bile duct tumors. Bile duct papillary tumors occurring with NETs are extremely rare. Since both IPNB and NET can cause biliary obstruction, bile duct dilation, and have varying degrees of malignant potential, aggressive surgical resection is the treatment of choice for these two types of tumors. The surgical method should be determined according to the lesion. The basic principle is consistent with that applied during cholangiocarcinoma surgery; that is, in addition to the removal of the primary site of the lesion, regional lymph node dissection should also be performed. If the lesion is located in the liver and is confined to the liver segment, lobe, or hemi-liver, the corresponding liver segmentectomy, lobectomy, or hepatectomy should be performed, and hilar lymph node dissection should be performed. If it is located in the hilar bile duct, radical surgery as is done for hilar cholangiocarcinoma should be performed. If it is located in the extrahepatic bile duct, radical treatment and radical pancreaticoduodenectomy as is done for extrahepatic cholangiocarcinoma should be performed. If the lesion involves one side of the liver and the extrahepatic bile duct, pancreaticoduodenectomy and corresponding hemi-hepatectomy are feasible. Liver transplantation and pancreaticoduodenectomy are theoretically feasible if the lesion involves the intrahepatic bile ducts extensively.12 For patients with unresectable NETs, arterial embolization chemotherapy and radiofrequency treatment can be considered. Postoperative adjuvant chemotherapy, targeted therapy, local radiotherapy, and somatostatin analogues can be used. These can improve symptoms and extend survival. 7, 13, 14 In this case, the tumor was located in the lower common bile duct, 2 cm from the duodenal papilla; therefore, radical pancreaticoduodenectomy (Whipple operation) was performed. Given that platinum-combined chemotherapy is recommended for small cell carcinomas, we resorted to administer VP-16 chemotherapy to this patient.15 However, he did not give his consent; therefore, it was impossible to evaluate the effect of chemotherapy on the disease. Due to the low incidence of NETs in the extrahepatic bile duct, there is currently no evidence of high-level evidence-based medicine for postoperative adjuvant therapy. Presently, some clinical studies have reported that sunitinib and everolimus are often used for NETs and can prolong the survival time of patients.15, 16 However, there is no report on their effectiveness in extrahepatic cholangiocarcinoma. Radiotherapy may be ineffective for cholangiocarcinoma. With the marketing of targeted drugs and tumor immunotherapy drugs in recent years, future studies can consider conducting gene testing for such patients, and use such treatments if conditions permit to investigate their effectiveness given that no report on this exists as at now.
IPNB progresses relatively slowly, and the prognosis is relatively good. It has been reported that the 5-year postoperative recurrence rate of benign IPNB is about 20%, and the overall 5-year disease-free survival rate (for benign and malignant) can reach 81%.17 However, primary NETs of the bile duct are often diagnosed late and have a poor prognosis due to tumor spread or metastasis.17
Papilloma of the bile duct with small cell neuroendocrine carcinoma is a rare disease, which is difficult to be diagnosed preoperatively. A combination of a perfect clinical examination, careful observation of imaging findings, and full preoperative evaluation help in formulating a reasonable surgical plan, especially in improving outcomes. Histochemistry is useful for diagnosis confirmation. Surgical resection is still the most effective treatment method, and it is currently the only treatment method to obtain potential efficacy and prolong disease-free survival.