Toru Furukawa

Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: recommendations of verona consensus meeting

BACKGROUNDnThere are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs).nnnDESIGNnAn international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations.nnnRESULTSn(1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term minimally invasive should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤ 0.5, > 0.5-≤ 1, > 1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of indeterminate/(suspicious) for invasion is acceptable for rare cases. (6) The term malignant IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic).nnnCONCLUSIONSnThese recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma

Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion.

Familial pancreatic cancer: Concept, management and issues

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

Relationship between pancreatic intraepithelial neoplasias, pancreatic ductal adenocarcinomas, and single nucleotide polymorphisms in autopsied elderly patients

We comparatively analyzed serially autopsied, elderly Japanese patients (nu2009=u20092205) with pancreatic intraepithelial neoplasias (PanINs) and pancreatic ductal adenocarcinomas (PDACs) on the basis of their pancreatic lesions, clinical information, and single nucleotide polymorphisms (SNPs). The incidence of PanIN‐1, −2, −3, and PDACs in these patients was 55%, 12%, 1.4%, and 2.4%, respectively. The occurrence of PanINs was associated with female sex, increasing age, and lower body mass index. We did not identify any common SNPs between PanINs and PDACs. There were no common SNPs associated with PanINs and PDACs between men and women. In previously reported pancreatic cancer‐associated SNPs, rs3790844 (NR5A2) showed a significant correlation with PDAC in our cohort. Six SNPs (rs7016880, rs10096633, rs10503669, rs12678919, rs17482753, rs328) that were correlated with blood lipid levels were associated with the risk for PDACs. Our data suggest that different clinicopathological characteristics and predispositions may affect pancreatic carcinogenesis in elderly Japanese patients.

Multicenter study of early pancreatic cancer in Japan

BACKGROUND/OBJECTIVESnThe diagnosis of early-stage pancreatic ductal adenocarcinoma (PDAC) is still challenging. We conducted a multicenter study to clarify the clinical features of early-stage PDAC in Japan.nnnMETHODSnWe collected patients with stage 0 and stage I PDAC according to the sixth edition of the Japanese Classification of Pancreatic Carcinoma. We retrospectively analyzed the clinical profiles including opportunities for medical examination, imaging modalities and findings, methods of cytological diagnosis, and prognosis according to the stages at diagnosis.nnnRESULTSnTwo hundred cases with Stage 0 and stage I PDAC were reported from 14 institutions, which accounted for approximately 0.7% and 3% of all PDAC cases, respectively. Overall, 20% of the early-stage PDAC cases were symptomatic. Indirect imaging findings such as dilatation of the main pancreatic duct were useful to detect early-stage PDAC. In particular, local fatty changes may be specific to early-stage PDAC. For preoperative pathologic diagnosis, cytology during endoscopic retrograde cholangiopancreatography was more commonly applied than endoscopic ultrasound fine-needle aspiration. Although the overall prognosis was favorable, new PDAC lesions developed in the remnant pancreas in 11.5% cases.nnnCONCLUSIONSnThis multicenter study revealed several key points concerning the diagnosis and management of early-stage PDAC, including screening of asymptomatic cases, importance of indirect imaging findings, application of cytology during endoscopic retrograde cholangiopancreatography, and the risk of carcinogenesis in the remnant pancreas.

High-grade dysplasia/carcinoma in situ of the bile duct margin in patients with surgically resected node-negative perihilar cholangiocarcinoma is associated with poor survival: a retrospective study

The clinical relevance of a high‐grade dysplasia/carcinoma in situ (HD/CIS)‐positive bile duct margin in perihilar cholangiocarcinoma (PHC) is unclear. We evaluated the surgical outcomes of PHC patients with HD/CIS.

Intracystic papillary neoplasm with an associated mucinous adenocarcinoma arising in Rokitansky–Aschoff sinus of the gallbladder

Intraepithelial neoplasias are preinvasive neoplastic lesions found throughout in the digestive system, and when such lesions are discovered in the gallbladder, they are referred to as intracystic papillary neoplasm (ICPN). In the gallbladder, mucinous adenocarcinoma is a rare histologic phenotype, and adenocarcinomas involving Rokitansky–Aschoff (RA) sinuses are uncommon, which were indeed found in a case reported here. A 64-year-old male presenting with upper abdominal pain demonstrated a spherical mass protruding outward from the gallbladder fundus in imaging studies. Laparoscopic cholecystectomy was performed, and the resected specimen revealed a subserosal cystic mass with a small communication with the gallbladder lumen. The cystic mass contained a gelatinous material without solid component. Histologically, the mass was consisted of subserosal cysts lined by atypical columnar mucinous epithelium with micropapillary growth and nuclear stratification. The neoplastic transformation was more pronounced toward the serosal side of the lesion where disruption of the cyst wall, intrastromal mucin lakes, and invasion of the neoplastic cells into surrounding stroma were observed. The epithelium was of intestinal lineage, which was supported by the positive immunoreactivity against CDX2 and MUC2. The cystic spaces were communicated with surrounding RA sinuses, which indicated that the tumor arose in the sinus. The pathological diagnosis was ICPN, intestinal type, with an associated mucinous adenocarcinoma arising in RA sinus.

ENBD is Associated with Decreased Tumor Dissemination Compared to PTBD in Perihilar Cholangiocarcinoma

BackgroundLittle is known regarding the risk of tumor dissemination when percutaneous biliary drainage is used before surgical resection of perihilar cholangiocarcinoma (PHC). We aimed to compare the incidence of tumor dissemination after preoperative endoscopic nasobiliary drainage (ENBD) with that after percutaneous transhepatic biliary drainage (PTBD) for PHC.MethodsData from 208 consecutive patients who underwent PHC resection between 2000 and 2013 were retrospectively analyzed. The influence of drainage type on incidence of tumor dissemination was examined. Seventy-six patients underwent ENBD (37%), 87 underwent PTBD (42%), and 45 underwent surgery without preoperative biliary drainage (WD, 22%).ResultsThe respective 2- and 5-year estimated cumulative incidences of tumor dissemination in the ENBD group (11.8/14.6%) were lower than in the PTBD group (28.8/35.9%, pxa0=xa00.003) and equivalent to that in the WD group (11.2/15.9%, pxa0=xa0NS). PTBD (hazard ratio [HR] vs. ENBD, 2.80) was an independent risk factor for postoperative tumor dissemination in the multivariate analysis. The 2- and 5-year disease-specific survival rates were higher in the ENBD group (67.6/47.3%) than in the PTBD group (56.6/27.8%, pxa0=xa00.032) and equivalent to that in the WD group (64.9/53.8%, pxa0=xa0NS). However, drainage type was not an independent risk factor in multivariate analysis of disease-specific survival.ConclusionFor patients with PHC, the associated risk of postoperative tumor dissemination in the ENBD group was lower than in the PTBD group and equivalent to that in the WD group. Thus, ENBD is the ideal procedure for preoperative biliary drainage.

Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma

Mutations in genes of the breast cancer susceptibility gene (BRCA) pathway, namely, BRCA1, BRCA2, and PALB2, can provide useful information for the efficacy of platinum-based or poly ADP-ribose polymerase inhibitors chemotherapeutic regimens. Pancreatic ductal adenocarcinoma (PDAC) is an important target for such precision chemotherapies because of its dismal prognosis. We analyzed mutations in the entire coding regions of the BRCA pathway genes, expression of breast cancer 2 (BRCA2), and mutations in hotspots of 50 cancer-associated genes in 42 surgically resected PDACs, and evaluated their associations with clinicopathological features. We identified 13 rare germline mutations in the BRCA pathway genes; 68 somatic mutations in KRAS, TP53, SMAD4, CDKN2A, GNAS, SMARCB1, and RB1; and 2 germline variations in MLH1. Among them, BRCA2S2148fs was known to be pathogenic. BRCA2R18H and BRCA2G2044V were enriched in tumor tissues. BRCA2K799R and BRCA2R2964T were novel germline variations. Patients harboring potentially deleterious mutations in the BRCA pathway genes showed significantly better prognosis than those with benign mutations or no mutation. These results indicate that rare germline variations in BRCA pathway genes could be found more frequently than previously anticipated and, more importantly, potentially deleterious mutations of them could be a favorable prognostic factor in patients with resectable PDACs.

Somatic mutations and increased lymphangiogenesis observed in a rare case of intramucosal gastric carcinoma with lymph node metastasis

Background and aim Intramucosal gastric adenocarcinoma of the well-moderately differentiated type only exhibits lymph node metastasis in extremely rare cases. We encountered such case and investigated both the lymphangiogenic properties and somatic mutations in the cancer to understand the prometastatic features of early-stage gastric cancer. Methods We quantitatively measured the density of lymphatic vessels and identified mutations in 412 cancer-associated genes through next-generation target resequencing of DNA extracted from tumor cells in a formalin-fixed and paraffin-embedded tissue. Functional consequence of the identified mutation was examined in vitro by means of gene transfection, immunoblot, and the quantitative real-time polymerase chain reaction assay. Results The intramucosal carcinoma was accompanied by abundant lymphatic vessels. The metastatic tumor harbored somatic mutations in NBN, p.P6S, and PAX8, p.R49H. The PAX8R49H showed significantly higher transactivation activity toward E2F1 than the wild-type PAX8 (P< 0.001). Conclusions Our data suggest that increased lymphangiogenesis and somatic mutations of NBN and/or PAX8 could facilitate lymph node metastasis from an intramucosal gastric carcinoma. These findings may potentially inform evaluations of the risk of developing lymph node metastasis in patients with intramucosal gastric cancer.