The most common form of cholangiocarcinomas associated with CBD are adenocarcinomas; NECs are rare. We searched PubMed for English-language reports describing NEC of the common bile duct associated with CBD and only two cases were reported. To the best of our knowledge, this is the third case of an NEC of the common bile duct associated with CBD to be reported. Pathological diagnoses of the previously reported cases were of well-differentiated NECs [5, 6].
Congenital bile duct dilatation
CBD is seen more often in female patients than in male patients (male-to-female ratio, 1:3). CBD is also common in Asian patients. Todani et al., categorized CBD into five main types, and almost all CBDs of types Ia, Ic, and IV-A are associated with pancreaticobiliary maljunction .
A proposed etiology of bile duct dilatation is an increase in the bile duct pressure of the narrow segment of the lower bile duct accompanied by pancreaticobiliary maljunction while the bile duct wall is immature, thereby resulting in dilation of the bile duct. Another hypothesis is that the primitive common bile duct proliferates asymmetrically in the early embryonic period, i.e., insufficient epithelial proliferation in the lower bile duct and excessive proliferation in the upper bile duct leads to stenosis of the lower bile duct and dilatation of the upper bile duct .
Pancreaticobiliary maljunction causes mixing and regurgitation of bile and pancreatic juices, which stagnate in the gallbladder and the bile duct, especially in the dilated common bile duct. This increases the cytotoxic potential for damage to the biliary epithelium under conditions of infection, inflammation, biliary stasis, decreased trypsin inhibitor concentrations, and the presence of enterokinase [5, 7, 8]. During repair, multiple alterations of oncogenes and tumor suppressor genes occur, and this could lead to the development of carcinomas through multistage interactions. Hyperplasia of the biliary or gallbladder epithelium is characteristic of pancreaticobiliary maljunction; moreover, mutations of the K-ras and p53 genes and overexpression of the p53 protein are observed in malignant as well as benign lesions of the biliary tract in patients with pancreaticobiliary maljunction. These changes are referred to as the “hyperplasia-carcinoma sequence” [9, 10].
One study reported that the incidence of cholangiocarcinoma was approximately 15% in Japanese patients with CBD. The incidence of cholangiocarcinomas after extrahepatic bile duct excision is 0.7%, although this is approximately 200 times higher than the incidence of cholangiocarcinoma in the general population in Japan [2, 3]. Another study reported that the overall incidence of cholangiocarcinoma with pancreaticobiliary maljunction with both a dilated and a nondilated bile duct, is 10.4%, which is more than 285 times higher than the risk in general population . Furthermore, the average age of patients with cholangiocarcinoma associated with pancreaticobiliary maljunction is 10 years lower than that of the general population [2, 11, 12].
Neuroendocrine carcinoma of the common bile duct
Biliary NEC represents 0.19% of all primary malignant tumors in the extrahepatic bile duct . It is estimated that over 50% of patients with gastroenteropancreatic NEC exhibit distant metastasis during initial diagnosis. Biliary NEC is relatively aggressive. In a review of 22 patients with biliary NEC, distant metastasis occurred in 16 cases on initial admission. Distant metastasis is present in all cases within one year after surgery, even though surgery is the mainstay of treatment for biliary NEC and is regarded as the curative option. Furthermore, the survival outcomes are poorer (in the decreasing order) for NECs that originate in the lungs, gastrointestinal tracts, and hepato-biliary-pancreatic systems . Terashima et al., reported that the response rate to chemotherapy in patients with extrapulmonary NEC was lower than that in patients with pulmonary NEC. In cases of extrapulmonary NEC, the hepato-biliary-pancreatic systems group showed the lowest response rate .
In many anatomical sites, neoplasms exist that exhibit both neuroendocrine and non-neuroendocrine elements, which can be present as morphologically distinct cell populations or be more intimately intermixed. The neuroendocrine elements of these “mixed” or “combined” neoplasms are most commonly NECs; the non-neuroendocrine components can be glandular, squamous, or of other lineages .
In our case, neuroendocrine components occupied 90% or more of the tumor’s invasive area, and few adenocarcinomatous components were found (Fig. 4A). In contrast, early adenocarcinomatous components were found on the mucosa of the tumor surface (Fig. 4B). This suggests that hyperplasia and dysplasia due to chronic inflammation of the bile duct mucosa initially result in adenocarcinomas, which subsequently transforms to NECs; however, in our case, a small extent of hyperplasia or dysplasia was noted on the noncancerous mucosa of the bile duct or gallbladder, differing from typical CBD. However, the concept of cancer stem cells is widely accepted as important in cancer development, with recent studies showing that cancer stem cells play important roles in the carcinogenesis of various types of cancer. In particular, several investigations have demonstrated that the different components of mixed neuroendocrine-non-neuroendocrine neoplasms are monoclonal, although their molecular signature is not identical to that of their relative counterparts when they present as separate neoplasms [17, 18].
Neuroendocrine carcinoma of common bile duct associated with congenital bile duct dilatation
We searched the PubMed database for reports in English language describing neuroendocrine carcinomas of the common bile duct associated with congenital bile duct dilatation and found two cases. One was a 6-year-old girl who underwent extrahepatic duct resection and hilar lymphadenectomy. The pathological diagnosis was a well-differentiated NEC; she was recurrence-free for two years without adjuvant chemotherapy. The other was a 28-year-old woman who underwent pancreaticoduodenectomy. The pathological diagnosis was a well-differentiated NEC (pT1N0M0 stageIA); she was recurrence-free for 3 years without adjuvant chemotherapy. Our patient was a 29-year-old woman who underwent pancreaticoduodenectomy. The pathological diagnosis was a poorly differentiated NEC (pT3aN1M0 stageIIB); she continues to undergo follow-up as an outpatient. In accordance with NCCN guidelines for small cell carcinomas of the lung, she received cisplatin at a dose of 60 mg/m2 on 1st day and irinotecan at a dose of 60 mg/m2 on 1st, 8th, and 15th days; administration of both drugs was repeated every 4 weeks for four cycles as adjuvant chemotherapy. She has not experienced recurrence in 14 months. The common feature in all three cases was that the patients were of the same gender. Ours is the only case to receive adjuvant chemotherapy for advanced disease.
In our case, it was probable that the adenocarcinoma first developed in the common bile duct with subsequent neuroendocrine differentiation. In contrast, the two previous reports did not clearly indicate whether their tumor included adenocarcinoma components; thus, NEC may have developed de novo in the common bile duct.