Masayuki Akita

Comparative clinicopathological study of biliary intraductal papillary neoplasms and papillary cholangiocarcinomas

The aim of this study was to achieve a better definition of intraductal papillary neoplasms of the bile duct (IPNBs).

IL-8 Expression in Granulocytic Epithelial Lesions of Idiopathic Duct-centric Pancreatitis (Type 2 Autoimmune Pancreatitis)

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P<0.001). In immunostaining, IL-8 expression was detected in the ductal/ductular epithelium (11/13; 85%) and infiltrating neutrophils or lymphocytes (12/12; 100%) in type 2 AIP, but was almost entirely negative in type 1 AIP (n=13; both, P<0.001). Although obstructive pancreatitis adjacent to pancreatic cancers (peritumoral pancreatitis) exhibited IL-8 expression in the epithelium (3/12; 25%) and inflammatory cells (10/12; 83%), expression levels were significantly lower than those in type 2 AIP (P<0.001 and 0.020, respectively). The presence of either GELs or IL-8-positive epithelium discriminated type 2 AIP from type 1 AIP or obstructive pancreatitis with 92% sensitivity and 92% to 100% specificity. Furthermore, CD3/IL-8-coexpressing lymphocytes were almost restricted to type 2 AIP. Interestingly, a similar pattern of IL-8 expression was also observed in colonic biopsies of ulcerative colitis. In conclusion, the overexpression of IL-8 may underlie the development of GELs in type 2 AIP, and IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary method for its diagnosis. The similar expression pattern of IL-8 in ulcerative colitis also suggests a pathogenetic link between the 2 conditions.

Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas

Intrahepatic cholangiocarcinomas were classified into two types based on their microscopic appearance. Tumors with histologic similarities to hilar cholangiocarcinomas (predominantly ductal adenocarcinomas with minor tubular components, if present, restricted to the invasive front) were defined as the perihilar type, whereas the others were classified as peripheral cholangiocarcinomas. Among the 47 cases examined in the present study, 26 (55%) were classified as the perihilar type, whereas 21 (45%) were the peripheral type. The perihilar type had higher pT stages and more frequently showed a periductal-infiltrating gross appearance and microscopic perineural infiltration than peripheral cholangiocarcinomas. The presence of low-grade biliary intraepithelial neoplasia in the adjacent bile ducts was only found in perihilar cholangiocarcinomas (6/21, 29%). The immunophenotype also differed between the two types with MUC5AC and MUC6 being more commonly expressed in the perihilar type. One-third of perihilar cholangiocarcinomas lacked the expression of SMAD4, suggesting SMAD4 mutations, whereas the loss of BAP1 expression and IDH1 mutations were almost restricted to the peripheral type (35 and 15%, respectively). Patients with perihilar cholangiocarcinoma had worse overall survival than those with peripheral cancer (P=0.027). A multivariate analysis identified the histologic classification as an independent prognostic factor (P=0.005, HR=3.638). Comparisons between intrahepatic and hilar cholangiocarcinomas also revealed that the molecular features and prognosis of perihilar cholangiocarcinomas were very similar to those of hilar cholangiocarcinomas. In conclusion, this histology-based classification scheme of intrahepatic cholangiocarcinomas will be useful and clinically relevant because it represents different underlying molecular features and has an independent prognostic value.

CD133 expression in well-differentiated pancreatic neuroendocrine tumors: a potential predictor of progressive clinical courses

The present study aimed to elucidate whether the stemness molecule, CD133, is expressed in well-differentiated pancreatic neuroendocrine tumors (PanNETs; World Health Organization grades 1 and 2) and establish its clinical relevance using 2 separate cohorts. In the first series (n = 178) in which tissue microarrays were available, immunohistochemistry revealed that CD133 was expressed in 14 cases (8%). CD133+ PanNETs had higher TNM stages (P < .01), more frequent lymphovascular invasion (P = .01), and higher recurrence rates (P = .01). In the second cohort (n = 56), the expression of CD133 and CK19 was examined in whole tissue sections. CD133 and CK19 were positive in 10 (18%) and 36 (64%) cases, respectively. CD133 expression correlated with higher pT scores (P < .01), the presence of microscopic venous infiltration (P = .03), and shorter disease-free periods (P < .01). When cases were divided into grade 1 and 2 neoplasms, patients with CD133+ PanNET continued to have shorter disease-free periods than did those with CD133- tumors in both groups (P < .01 and P = .02, respectively). Although CK19+ cases had shorter disease-free periods than did CK19- cases in the whole cohort (P = .02), this difference was less apparent in subanalyses of grade 1 and 2 cases. CD133 expression also appeared to be an independent predictive factor for tumor recurrence in a multivariate analysis (P = .018). The CD133 phenotype was identical between primary and metastatic foci in 17 of 18 cases from which tissues of metastatic deposits were available. In conclusion, the combination of CD133 phenotyping and World Health Organization grading may assist in stratifying patients in terms of the risk of progressive clinical courses.

High-grade PanIN presenting with localised stricture of the main pancreatic duct: A clinicopathological and molecular study of 10 cases suggests a clue for the early detection of pancreatic cancer

This study aimed to identify the pathological features of high‐grade PanIN that presents with imaging‐detectable abnormalities.

Interleukin-33 overexpression reflects less aggressive tumour features in large-duct type cholangiocarcinomas

The aim of the present study was to elucidate the clinicopathological significance of interleukin (IL)‐6 and IL‐33 expression in intrahepatic cholangiocarcinomas (iCCAs) and perihilar cholangiocarcinomas (pCCAs).

SOX2-silenced squamous cell carcinoma: a highly malignant form of esophageal cancer with SOX2 promoter hypermethylation

This study originally aimed to investigate whether the overexpression of SOX2 is associated with the poor prognosis of patients with squamous cell carcinoma of the esophagus. However, we unexpectedly found that esophageal squamous cell carcinomas completely lacking SOX2 expression showed distinct pathologic features and highly aggressive clinical courses. The study cohort consisted of 113 consecutive patients with esophageal squamous cell carcinoma who underwent surgical resection without neoadjuvant therapy. Immunostaining on tissue microarrays and whole sections revealed that 8/113 (7%) cases were entirely negative for this transcriptional factor. SOX2-negative cancers were histologically less differentiated (P=0.002) and showed higher pT and pStages (P=0.003 and 0.007, respectively) than SOX2-positive cases. A remarkable finding was widespread lymphatic infiltration distant from the primary invasive focus, which was observed in 4 SOX2-negative cancers (50%), but none of the SOX2-positive cases. All separate dysplastic lesions observed in SOX2-negative cases were also SOX2-negative. The negative expression of SOX2 appeared to be an independent poor prognostic factor (OR=7.05, 95% CI=1.27–39.0). No mutations were identified in the coding or non-coding regions of SOX2. Fluorescent in situ hybridization did not show any copy-number variations in this gene. Since the SOX2 promoter contains an extensive CpG island, SOX2-negative cases underwent methylation-specific PCR, which disclosed promoter hypermethylation in all cases. In conclusion, SOX2-silenced squamous cell carcinomas of the esophagus appear to be a minor, but distinct form of malignancy characterized by extensive lymphatic invasion, a poor prognosis, and potential association with multiple SOX2-negative neoplastic lesions. The hypermethylation of the promoter region is seemingly a critical epigenetic event leading to SOX2 silencing.

Preoperative Cholangitis Affects Survival Outcome in Patients with Extrahepatic Bile Duct Cancer

BackgroundIt remains controversial whether preoperative cholangitis affects long-term outcomes after resection in patients with extrahepatic bile duct cancer.MethodsA total of 107 patients with extrahepatic bile duct cancer who underwent resection with curative intent from 2008 to 2014 were retrospectively reviewed. Patients were categorized into two groups according to the presence or absence of preoperative cholangitis. Clinicopathological variables and long-term outcomes were compared in the two groups.ResultsIn the preoperative cholangitis group, the rate of preoperative biliary drainage, the number of tube changes and/or additions, and the rate of lymph node metastasis were higher compared to the no-cholangitis group. Overall survival and disease-free survival were significantly worse in the cholangitis group compared to the no-cholangitis group (p = 0.022, p = 0.007). A poorer prognosis was not observed with an increasing grade of cholangitis in Tokyo Guidelines 2013 (p = 0.09). A multivariate logistic regression analysis revealed that the preoperative cholangitis was an independent prognostic factor for extrahepatic bile duct cancer.ConclusionPreoperative cholangitis is an independent prognostic factor in patients with extrahepatic bile duct cancer regardless of the severity of the cholangitis.

Mucinous cystic neoplasms of the liver and pancreas: Relationship between KRAS driver mutations and disease progression

To compare the oncogenic mutation status among mucinous cystic neoplasms (MCNs) of different histological grades and between liver and pancreatic MCNs.