Yoshitsugu Nakanishi

Endoscopic retrograde cholangiography versus peroral cholangioscopy to evaluate intraepithelial tumor spread in biliary cancer

BACKGROUND AND STUDY AIMS Localized-type bile duct carcinoma (LBDC) is often accompanied by extensive intraepithelial tumor spread (ITS) of 2 cm or more, which makes radical resection more difficult. This retrospective case review compares the diagnostic accuracy of endoscopic retrograde cholangiography (ERC) and peroral cholangioscopy (POCS) to detect ITS beyond the visible LBDC. PATIENTS AND METHODS Forty-four consecutive patients with LBDC diagnosed between April 2004 and October 2008 who underwent radical resection with histopathological analysis were included in this study. Extensive ITS was found histopathologically in one-third of the cases (32 %). The outcome parameters were the presence or absence of extensive ITS and the extent of extensive ITS proximal and distal to the main tumor. RESULTS In six cases it was not possible to pass the cholangioscope through the tumor sites. ERC correctly identified the presence of extensive ITS in 11/14 cases and did not yield any false-positive results. The three cases in which ERC was negative were all correctly identified by POCS plus biopsy since the cholangioscope could be passed in all three cases. The extent of extensive ITS was correctly diagnosed by ERC alone, ERC with POCS, and ERC with POCS plus mapping biopsy in 22 %, 77 %, and 100 % of cases, respectively. CONCLUSIONS The presence of extensive ITS was correctly detected in 80 % of cases by ERC alone. POCS with mapping biopsy provided perfect diagnostic accuracy not only of the presence or absence but also of the extent of extensive ITS. However, POCS has the limitation that the cholangioscope cannot be passed through the tumor sites in approximately 15 % of cases.

Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm

Cholangiocarcinoma of intrahepatic and extrahepatic bile ducts has a multistep carcinogenesis. Two premalignant lesions have been suggested for invasive cholangiocarcinoma: biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. How the carcinogenetic process differs between biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct is not clear. In this study, we performed a pathological study to reveal the expression of key molecules related to the cell cycle during 2 carcinogenetic lineages. We immunohistochemically examined the expression of p21, p53, cyclin D1, and Dpc4 in a total of 89 cases: nonneoplastic biliary epithelium, biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and invasive cholangiocarcinoma. The expression of p21, p53, and cyclin D1 was up-regulated with histological progression in both biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct, whereas Dpc4 expression was down-regulated in these 2 lineages. In biliary intraepithelial neoplasia, p21 expression was significantly up-regulated early on. In contrast, levels of all molecules changed gradually in intraductal papillary neoplasm of the bile duct. Changes in p53 expression during histological progression differed significantly between biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. p53 expression was dramatically up-regulated at the invasive stage of biliary intraepithelial neoplasia, whereas it was quite low in noninvasive biliary intraepithelial neoplasia. In contrast, p53 expression was already up-regulated in low-grade intraductal papillary neoplasm and reached a plateau in high-grade intraductal papillary neoplasm and invasive cholangiocarcinoma. This study suggested p21, p53, cyclin D1, and Dpc4 to be involved in the carcinogenesis of both biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. p53 expression was regulated differently in biliary intraepithelial neoplasia compared with intraductal papillary neoplasm of the bile duct.

Intraductal oncocytic papillary neoplasm of the bile duct: the first case of peribiliary gland origin

We report herein the first case of intraductal oncocytic papillary neoplasm of the bile duct arising from a peribiliary gland of the left hepatic duct. The patient was a 63-year-old Japanese man. Radiological and cholangioscopic examinations revealed intraductal tumor of the left hepatic duct. After pathological diagnosis of adenocarcinoma by cholangioscopic biopsy, a surgical hepatobiliary resection was performed. Pathological examination revealed papillary tumor in the left hepatic duct. Histologically, the tumor was identified as papillary neoplasm comprising oncocytic cells and delicate fibrovascular cores. Interestingly, this tumor originated from the cystic space in the bile duct wall. This cystic space was histologically identified as a cystically dilated peribiliary gland. Carcinoma in situ was observed in this cystic peribiliary gland at the bottom of the tumor, but not on any areas of biliary epithelium. This case suggests that intraductal papillary neoplasm can arise from both biliary epithelium and peribiliary glands.

Intraductal papillary neoplasm arising from peribiliary glands connecting with the inferior branch of the bile duct of the anterior segment of the liver

Intraductal papillary neoplasms of the bile duct are generally thought to arise from neoplastic papillary proliferation of epithelial cells lining the bile duct. We herein report a case with findings that strongly suggested that the biliary cystic tumor might have derived from a peribiliary gland. A 69‐year‐old female was found to have a cystic lesion with intracystic protrusions at the anterior segment of the right hepatic lobe and underwent hepatic anterior segment resection. Fluoroscopy of the resected specimen injected with contrast medium into the cyst revealed a connection between the cystic lesion and the bile ducts. The cyst was multilocular in appearance. On microscopic examination, the cyst was located within the portal tract of the inferior branch of the anterior segment and connected with the inferior branch of the bile duct. The wall of the hepatic cyst lacked an ovarian‐like stroma. The tumor was composed of papillary and glandular components, and the tumor cells were similar to gastric foveolar and pyloric gland epithelia and regarded as adenoma. These tumor cells were positive for MUC 5AC, MUC6, and HIK1083. The tumor was finally diagnosed as an intraductal papillary neoplasm of the bile duct (adenoma, gastric type) arising from a peribiliary gland.

Prognostic Impact of Regional Lymph Node Micrometastasis in Patients With Node-Negative Biliary Cancer

Objective:To immunohistochemically identify regional lymph node micrometastases in patients with regional node-negative biliary cancer who underwent curative resection, and to evaluate their clinical significance. Summary Background Data:The clinical significance of immunohistochemically detected lymph node micrometastasis has recently been evaluated in various tumors. However, few reports have focused on this issue with regard to biliary cancer. Methods:A total of 1421 regional lymph nodes from 151 patients with biliary cancer with negative regional nodes (as determined by conventional methods) were immunostained with antibody against cytokeratins 7 and 8 (CAM5.2). Prognostic impact was evaluated among patients with no metastasis, micrometastasis, and obvious metastasis detected by hematoxylin and eosin staining. Immunostained tumor foci were classified as small micrometastasis or large micrometastasis according to size (above or below 0.2 mm). Results:CAM5.2-positive occult carcinoma cells in regional lymph nodes were detected in 33 (22%) of 151 patients and 49 (3%) of 1421 regional lymph nodes. Small micrometastases were detected in 23 patients, whereas large micrometastases were found in 10 patients. Survival for patients with micrometastasis was significantly worse than that for patients without (P = 0.0051), but was significantly better than that for patients with overt metastasis (P = 0.0092). No significant difference in postoperative survival was seen between patients with small and large micrometastases (P = 0.4221). Conclusions:Occult cancer cells were present in regional lymph nodes of 22% patients with regional node-negative biliary cancer, and were associated with significantly worse survival. Patients with micrometastases should be treated as carefully as node-positive patients.

Primary acinar cell carcinoma of the ampulla of Vater.

Acinar cell carcinoma of the pancreatobiliary system is a relatively rare malignant neoplasm arising usually in the pancreatic parenchyma. We experienced a 68-year-old woman who presented with obstructive jaundice due to an ampullary mass 1.0 cm in diameter, detected by abdominal computed tomography and endoscopic examination. The patient underwent a curative surgical operation, and histopathological examination revealed that the tumor was confined to the ampulla of Vater with no continuity to the pancreatic parenchyma. The tumor cells showed acinar or tubular arrangement with eosinophilic to basophilic granular cytoplasm, findings identical to those of acinar cell carcinoma of the pancreas. Immunohistochemically, the tumor cells were positive for lipase. From these findings, we concluded that the tumor was primary acinar cell carcinoma arising in the ampulla of Vater, probably originating from heterotopic pancreatic tissue. This is the first reported case of primary acinar cell carcinoma in the ampulla of Vater.

New Invagination Procedure for Pancreaticojejunostomy Using Only Four Sutures: Reply

Background Pancreaticoenterostomy remains one of the most stressful parts of pancreatoduodenectomy. We introduce herein a new convenient and secure invagination procedure for pancreaticojejunostomy.

Inadvertent Ingestion of a Press-Through Package Causing Perforation of the Small Intestine within an Incisional Hernia and Panperitonitis

A 90-year-old woman was admitted to the emergency department of our hospital with abdominal pain and a fever of up to 39°C. She had a history of hysterectomy about 30 years previously, and redness and swelling were seen at the abdominal median scar. Serum biochemistry showed minor elevation of C-reactive protein and creatine phosphokinase. Abdominal computed tomography (CT) showed an edematous intestinal tract image over the median abdominal wall. Incarcerated incisional hernia and intestinal necrosis were suspected. Therefore, emergency surgery was performed. On laparotomy, abundant purulent ascitic fluid was found. The small intestine was incarcerated about 100 cm orally from the terminal ileum, and a 2-mm perforation was present in the incarcerated small intestine. In addition, some white areas measuring 1 mm were found in the small intestinal wall. A press-through package (PTP) of a tablet was confirmed in the intestinal tract near the perforated area. We removed the PTP through the perforation and performed direct suture. Postoperatively, we retrospectively reviewed the CT image and found a high-density shadow which seemed to represent the PTP.

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations

BACKGROUND & AIMS Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape. METHODS We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features. RESULTS We identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients. CONCLUSIONS BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information. LAY SUMMARY We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition.

Spindle Cell-Type Undifferentiated Carcinoma of the Common Bile Duct of the Hepatic Hilus: Report of a Case

Spindle cell-type undifferentiated carcinoma arising from the extrahepatic bile duct is extremely rare. We herein report a case of this type of carcinoma in the common bile duct of the hepatic hilus. A 59-year-old man was admitted to our hospital complaining of jaundice. The laboratory data revealed an elevation of the serum carbohydrate antigen 19–9 level. Cholangiography revealed a complete obliteration of the left hepatic bile duct and stenosis of the bile duct from the superior to the right hepatic bile duct. Computed tomography showed the tumor to measure 15 × 12 mm in the hepatic hilus, with the obliteration of the right to main trunk of the portal vein and a swollen lymph node in the hepato-duodenum ligament. Arteriography revealed a kink of the right hepatic artery; therefore an encasement of the right hepatic artery was suspected. We preoperatively diagnosed hilus bile duct carcinoma and scheduled a right trisection hepatectomy. Intraoperative frozen sections taken from the tumor and tissues around the hepatic arteries showed spindle and inflammatory cells; therefore an inflammatory pseudotumor was diagnosed intraoperatively. As the right hepatic bile duct was occluded, a right lobe hepatectomy was performed. However, a permanent section revealed both spindle cells and poorly differentiated tubular adenocarcinoma cells positive for CAM5.2, AE1/AE3, and vimentin. On the basis of these findings, the tumor was finally diagnosed to be spindle cell-type undifferentiated carcinoma. Unfortunately, the patient died of pulmonary infarction 11 days after the operation.