BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasm (MINEN) is a rare disease and there is scarce literature on its diagnosis, treatment, and prognosis. We encountered two unusual cases of MINEN in the biliary tract, one in the ampulla of Vater and the other in the distal bile duct. In this report, we describe the clinical course of these two cases in detail.
METHODS: Case 1: A 69-year-old woman presented with a chief complaint of epigastric pain. When endoscopic sphincterotomy and retrograde biliary drainage were performed for gallstone pancreatitis, an ulcerated lesion was found in the ampulla of the Vater. Based on the biopsy results, the lesion was diagnosed as the ampulla of Vater carcinoma and subtotal stomach-preserving pancreatoduodenectomy (SSPPD) was performed. Postoperative histopathological examination revealed the coexistence of adenocarcinoma and neuroendocrine carcinoma components, consistent with the diagnosis of MINEN. In addition, lymph node metastasis was found on the dorsal side of the pancreas and the metastatic component was adenocarcinoma. Adjuvant chemotherapy with etoposide and cisplatin was administered for 6 months, and presently the patient is alive without recurrence 64 months after surgery. Case 2: A 79-year-old man presented with a chief complaint of anorexia. Cholangiography showed severe stenosis of the distal bile duct. A biopsy was conducted from the stenotic lesion and it revealed the lesion to be adenocarcinoma. A diagnosis of distal bile duct carcinoma was made, and SSPPD was performed. Histopathological examination revealed the coexistence of adenocarcinoma and neuroendocrine carcinoma components, and the tumor was confirmed as MINEN of the distal bile duct. No adjuvant chemotherapy was administered due to the poor performance status. 7 months later, the patient was found to have a liver metastasis.
CONCLUSIONS: We experienced two valuable cases of biliary MINEN. To identify better treatments, it is important to consider the diversity of individual cases and to continue sharing a variety of cases with different presentations.

According to the current 8th edition of the American Joint Committee of Cancer (AJCC), the T category of distal cholangiocarcinomas is classified based on the depth of invasion (DOI) (T1, < 5 mm; T2, between 5 and 12 mm; T3, > 12 mm). In consideration of the discrepancies between previous studies about the prognostic significance, we aimed to validate the current AJCC T staging system of distal cholangiocarcinomas. DOI was measured using three different methods: DOI1, DOI2, and DOI3. DOI1 was defined and stratified according to the AJCC 8th edition. DOI2 was measured as the distance from an imaginary curved line approximated along the distorted mucosal surface to the deepest invasive tumor cells. DOI3 was defined as the total tumor thickness. DOI2 and DOI3 were also divided into three categories using the same cut-off points as in the AJCC 8th edition. We compared these three DOI methods to the AJCC 7th edition as well. In contrast with the AJCC 7th edition, all three groups showed a correlation with patients\' overall survival. Above all, the DOI2 group demonstrated the best significance in multivariate analysis. However, when the C indices were compared between these groups, differential significance proved to be negligible (DOI1 vs DOI2, p = 0.915; DOI2 vs DOI3, p = 0.057). Therefore, the measurement of DOI does not need to be rigorously and stringently performed. In conclusion, we showed that the current T classification system better correlates with the overall survival of patients with distal cholangiocarcinomas than the previous system.

Identifying the accurate origin of periampullary cancers is important because different origins may trigger different clinicopathological behaviors. The presence of intraepithelial precursor lesions, including high-grade pancreatic intraepithelial neoplasias (PanINs) and/or high-grade biliary intraepithelial neoplasias (BilINs), may be suggestive of the origin of the periampullary carcinoma in challenging cases. To prove the usefulness of high-grade intraepithelial precursor lesions in identifying the origin of ambiguous periampullary cancers, the status and grades of PanINs and BilINs were evaluated in 256 periampullary carcinomas with a well-defined cancer origin as a test set, including 114 pancreatic cancers, 82 distal bile duct cancers, 54 ampullary cancers, and 6 duodenal cancers. One hundred twelve periampullary carcinomas with clinically equivocal epicenter either by radiologic imaging or by endoscopic finding used as a validation set. High-grade PanINs were found more commonly in pancreatic cancers than in distal bile duct, ampullary, and duodenal cancers both in test (P = .002) and validation sets (P < .001). Similarly, high-grade BilINs were identified more frequently in distal bile duct cancers than in ampullary, pancreatic, and duodenal cancers both in test (P < .001) and validation sets (P = .039). High-grade PanINs were found most commonly in pancreatic cancers, whereas high-grade BilINs were seen most frequently in distal bile duct cancers. In addition, both high-grade PanINs and high-grade BilINs are uncommonly noted in ampullary or duodenal cancers. The recognition of high-grade intraepithelial lesions can help identify the primary origin of periampullary cancers, especially when the epicenter of the periampullary cancer is ambiguous.

BACKGROUND: Mixed adenoneuroendocrine carcinomas (MANECs) of the distal bile duct are extremely rare, and only a few cases have been reported in the English literature.
METHODS: An 82-year-old man was referred to our hospital for increasing biliary enzymes. Abdominal computed tomography (CT) showed enlargement of the intrahepatic bile ducts and stenosis of the distal bile duct. Endoscopic retrograde cholangiopancreatography showed stenosis of the distal bile duct and a high-density signal at the same site on diffusion weighted imaging. PET-CT showed increased FDG accumulation (SUVmax: 4.5) at the distal bile duct stenosis. Biopsy specimens obtained by endoscopic ultrasonography-guided fine-needle aspiration revealed adenocarcinoma. The patient was diagnosed with adenocarcinoma of the distal bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection. The resected distal bile duct tumor was 18×14×12mm in diameter. Hematoxylin and eosin staining revealed a composite carcinoma with adenocarcinoma and non-adenocarcinoma elements. The non-adenocarcinoma component stained positive for synaptophysin and chromogranin A. The Ki-67 labeling index was 37%. The non-adenocarcinoma component was therefore diagnosed as a neuroendocrine carcinoma. The two composite carcinoma was diagnosed as MANEC of the distal bile duct. The patient was treated with surgery alone and he remained disease-free for 7 months after the surgery.
CONCLUSIONS: The treatment of MANECs of the bile duct remains controversial and the prognosis is poor.
CONCLUSIONS: There is no standard treatment for MANECs of the bile duct. Larger studies are required to establish standard treatment regimens.

OBJECTIVE: We investigated the prognostic value of clinicopathological factors in patients with a distal bile duct adenocarcinoma after curative resection.
METHODS: This retrospective study included 25 patients who underwent (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) before surgery. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured using FDG-PET/CT. FDG-PET/CT parameters and other clinicopathological factors were assessed to evaluate survival.
RESULTS: Univariate survival analysis showed that high TLG, high MTV, and high SUVmax were significant prognostic predictors for poor overall survival. For progression-free survival, high TLG and large tumor size were significant predictors for a poor prognosis. After multivariate survival analysis, only high TLG was an independent prognostic predictor for poor overall survival (p=0.025).
CONCLUSIONS: Preoperative assessment of TLG by FDG-PET/CT might be a useful prognostic predictor in patients with a distal bile duct adenocarcinoma after curative resection.

Large-cell neuroendocrine carcinoma (LCNEC) in the distal bile duct is very rare and different from common distal bile duct adenocarcinoma. A 77-year-old man was admitted with obstructive jaundice. Severe stenosis of the distal bile duct was revealed by percutaneous transhepatic cholangiography. Subtotal stomach-preserving pancreaticoduodenectomy was performed. A tumor measuring 1.8 cm in diameter was located in the distal bile duct. Both histopathological and immunohistochemical examination of the resected specimen revealed features of LCNEC of the bile duct. The patient developed multiple liver metastases, lung metastases, and local recurrence and died of disease 3 months after the operation. The clinical behavior of LCNEC in the distal bile duct appears to be highly aggressive with early metastases and a fatal outcome.