Neuroendocrine tumours are rare tumours with variable malignant potential. First described as carcinoids by Lubarsch in1888, latest WHO classification of 2019 divides them into well differentiated NETs of various grades (1to 3) and aggressive NEC based upon the differentiation and biologic aggression [5, 6]. Primary extrahepatic biliary tract (EHBT) NETs are uncommon, probably due to scarce presence of enterochromaffin cells in the bile duct [2]. Though Pilz reported the first case of carcinoid tumour of the common bile duct in 1961, there is limited literature on primary NETs of biliary origin. [7] Here we share our experience with four cases of resectable primary extrahepatic biliary NETs out of which three turned out to be grade II NET and one had NEC.
The etiology of biliary NETs is poorly understood. With no proven predisposing factors, it is hypothesised that chronic inflammation of biliary system arising from stones or congenital malformation induces intestinal metaplasia leading to malignancy [8, 9]. Michalopoulos et al found that 19.2% cases had associated cholelithiasis. Association with Von Hippel-Lindau syndrome, Multiple Endocrine Neoplasia (MEN-I) syndrome, or the Zollinger-Ellison syndrome has also been reported [10].
The extrahepatic biliary NETs are more common in females with a male to female ratio of 1: 1.5. In our series also 3 out of 4 patients were females. The median age in our series was 46 years which is same as that reported in literature and lesser than that for cholangiocarcinoma [10, 11]. Clinically, they most commonly present with biliary obstruction (100% in our series) but in recent times they are increasingly being diagnosed as incidental finding on cross sectional imaging [12]. Although NETs have the potential to secret neuropeptide hormones, the EHBT NETs are usually non-functioning and carcinoid syndrome is very rare even in metastatic disease [11].
Despite technical advances, establishing the diagnosis of extrahepatic biliary NETs preoperatively is painstakingly difficult. In most cases it comes across as a histopathological surprise. The radiological differentiation between the closest differential i.e. cholangiocarcinoma and biliary NETs is challenging due to similarities in the imaging findings. However, biliary NETs have been found to be hyper dense in arterial phase and more localized to the primary location without invading the surrounding structures than their cholangiocarcinoma counterparts [13]. Brush cytology specimen obtained via ERCP, Percutaneous transhepatic cholangiography or endoscopic ultrasound guided FNAC can provide the histological diagnosis but this potential is marred by the high false negative rates owing to the submucosal location of these tumours [4, 14]. Achieving preoperative tissue diagnosis is desirable in NETs as it helps in selecting the modality for further staging in the form of DOTA PET and/or FDG PET scans. We could achieve preoperative histological diagnosis in two of the four patients which lead to further staging by DOTA PET scans. Though the prognostic value of Chromogranin A has not been established, it has been used to monitor the treatment response assessment and to detect recurrence in follow up. [15]
Surgical resection remains the only curative option for these tumours with the extent of resection determined by the location of the tumour. While mid CBD NETs can be treated with extrahepatic biliary tract excision, distal involvement may require pancreaticoduodenectomy to achieve adequate margins. Similarly, proximal hepatic duct involvement may warrant a hepatectomy to achieve R0 resection. Regional periportal lymphadenectomy has been advocated by National Comprehensive Cancer Network guidelines and some authors [16]. In current series, three patients underwent EHBTE while one required additional right hepatectomy to achieve free margins. R0 resection was obtained in all the patients. Regional periportal nodal dissection was also done in all the cases. Role of neoadjuvant therapy for Biliary NETs is still not clearly defined but adjuvant chemotherapy with Cisplatin and Etoposide has been shown to have good results in cases of high grade NET (grade 3) and NEC [16, 17]. For locally advanced unresectable or metastatic extrahepatic biliary NETs, many treatment options like systemic chemotherapy, somatostatin analogues, liver directed therapies such as chemoembolisation or radioembolisation, peptide receptor nucleotide therapy to Liver transplantation have been described.[18]
The prognosis of biliary NETs varies as per their biologic aggressiveness. Distinction between NETs and NECs is made on the basis of nuclear atypia, mitoses and necrosis. The well differentiated NETs have organoid architecture and uniform nuclear features and may have minimal necrosis, while NECs are often seen in sheets and less nested pattern and further classified into Small cell NEC and Large cell NEC. While low grade I, II NETs tend to be indolent and slow growing with good prognosis, higher grade III NETs and NECs are aggressive with poor prognosis. Low grade NETs have shown to have excellent survival after radical resection with a 10-year survival of 80% whereas the poorly differentiated NEC has a dismal prognosis with majority of the patients succumbing to the disease within 1 year of surgery and a median survival of 9.6 months [19, 20]. In our series, the patient with NEC had progression on chemotherapy with overall survival of 15 months. In comparison, other patients with grade II NETs are recurrence free with one person at 75 months and two others at 8 months follow up each.
In conclusion, preoperative differentiation between cholangiocarcinoma and biliary NETs remains difficult despite all technological advances. However, preoperative diagnosis is desirable as it can lead to further staging in the form of functional DOTA-PET or FDG PET scans enabling comprehensive decision making. Radical resection with regional lymphadenectomy is curative treatment for biliary NETs especially for well differentiated tumours and has good prognosis. Poorly differentiated NEC is rare, aggressive variant with dismal prognosis which needs to be managed with multidisciplinary approach.