Yutaka Atomi

Intraductal papillary mucinous tumors of the pancreas: imaging studies and treatment strategies.

OBJECTIVE We analyzed clinicopathologic and imaging features and the prognosis of intraductal papillary mucinous tumor (IPMT) of the pancreas to identify imaging findings indicative of malignancy and to establish the optimal treatment strategy. SUMMARY BACKGROUND DATA In IPMT, preoperative differentiation between adenoma and adenocarcinoma is often difficult. Appropriate treatment based on pathologic study and surgical outcome has not been adequately documented. METHODS Forty-one patients with IPMT underwent surgery; 15 with adenoma and 26 with adenocarcinoma; main duct type in 13, combined type in 12, and branch duct type in 16. RESULTS In malignant IPMT, deep invasion was found in 62% and lymph node metastasis in 23% (peripancreatic nodes in 19% and distant nodes in 4%). Tumors with mural nodules (86%) had a significantly higher incidence of carcinoma than tumors without nodules (37%). IPMT with a main pancreatic duct > or =15 mm or tumor diameter > or =30 mm (branch duct type) showed a high prevalence of adenocarcinoma. Main duct (54%) and combined (58%) type tumor, and tumors with mural nodules (64%) often showed invasion. All five branch duct tumors less than 30 mm without nodules were adenomas. However, imaging studies could not definitely distinguish adenocarcinomas from adenomas. Complete resection was possible for all adenomas and 88% of adenocarcinomas. Five-year survival rates for patients with adenomas and adenocarcinomas were 100% and 82%, respectively. CONCLUSIONS IPMT has a favorable prognosis, regardless of deep invasion or node metastasis. IPMT requires peripancreatic node dissection in addition to complete tumor excision. Node dissection may be omitted for branch duct tumors less than 30 mm without mural nodules.

Autophagy Is Activated in Colorectal Cancer Cells and Contributes to the Tolerance to Nutrient Deprivation

Several types of cancer cells, including colorectal cancer-derived cell lines, show austerity, the resistance to nutrient starvation, but exactly how cancer cells obtain energy sources under conditions in which their external nutrient supply is extremely limited remains to be clarified. Because autophagy is a catabolic process by which cells supply amino acids from self-digested organelles, cancer cells are likely to use autophagy to obtain amino acids as alternative energy sources. Amino acid deprivation-induced autophagy was assessed in DLD-1 and other colorectal cancer-derived cell lines. The autophagosome-incorporated LC3-II protein level increased after treatment with a combination of autolysosome inhibitors, which interferes with the consumption of autophagosomes. Autophagosome formation was also morphologically confirmed using ectopically expressed green fluorescent protein-LC3 fusion proteins in DLD-1 and SW480 cells. These data suggest that autophagosomes were actively produced and promptly consumed in colorectal cancer cells under nutrient starvation. Autolysosome inhibitors and 3-methyl adenine, which suppresses autophagosome formation, remarkably enhanced apoptosis under amino acid-deprived and glucose-deprived condition. Similar results were obtained in the cells with decreased ATG7 level by the RNA interference. These data suggest that autophagy is pivotal for the survival of colorectal cancer cells that have acquired austerity. Furthermore, autophagosome formation was seen only in the tumor cells but not in the adjacent noncancerous epithelial cells of colorectal cancer specimens. Taken together, autophagy is activated in colorectal cancers in vitro and in vivo, and autophagy may contribute to the survival of the cancer cells in their microenvironment.

Cystic neoplasm of the pancreas: a Japanese multiinstitutional study of intraductal papillary mucinous tumor and mucinous cystic tumor.

Abstract: The Japan Pancreas Society performed a multiinstitutional, retrospective study of 1379 cases of intraductal papillary mucinous tumor (IPMT) and 179 cases of mucinous cystic tumor (MCT) of the pancreas. Clinicopathologic features and postoperative long-term outcomes were investigated. IPMT were most frequently found in men and in the head of the pancreas. In contrast, all patients with MCT were women. Ovarian-type stroma were found in only 42.2% of the MCT cases. Prognostic indicators of malignant IPMT included advanced age, positive symptoms, abundant mucous secretion, presence of large nodules and/or large cysts, remarkable dilatation of the main pancreatic duct, and main duct- or combined-type IPMT. Advanced age, positive symptoms, and presence of large nodules and/or large cysts were predictive of malignant MCT. The 5-year survival rate of IPMT patients was 98%–100% in adenoma to noninvasive carcinoma cases, 89% in minimally invasive carcinoma cases, and 57.7% in invasive carcinoma cases. The 5-year survival rate of MCT patients was 100% in adenoma to minimally invasive carcinoma cases and 37.5% in invasive carcinoma cases. In conclusion, IPMT and MCT show distinct clinicopathologic and prognostic differences. The results from this study may contribute to the diagnosis and treatment of IPMT and MCT.

Endoscopic ultrasonography for diagnosing choledocholithiasis: a prospective comparative study with ultrasonography and computed tomography

BACKGROUND We assessed the diagnostic usefulness of endoscopic ultrasonography (EUS) for choledocholithiasis. METHODS A prospective series of 155 patients with suspected choledocholithiasis all underwent EUS, conventional ultrasonography, CT, and ERCP. In 142 patients with a clear cholangiogram on ERCP, we analyzed the capability of EUS to image the extrahepatic bile duct and to identify choledocholithiasis, compared with ultrasonography and CT. RESULTS No complications were encountered in performing EUS. In 51 patients, ERCP demonstrated bile duct stones, which were confirmed at endoscopic sphincterotomy or surgery. The extrahepatic bile duct was wholly displayed in 96% by EUS, in 60% by ultrasonography, and in 80% by CT. EUS (96%) was more sensitive than ultrasonography (63%) and CT (71%) for detecting choledocholithiasis (p < 0.001). Although ultrasonography and CT were poorly diagnostic for choledocholithiasis in patients with small stones or those with a nondilated common bile duct, EUS was able to accurately detect choledocholithiasis regardless of the size of stones or the diameter of the bile duct. The specificity of EUS (100%) was higher than those of ultrasonography (95%) and CT (97%). CONCLUSIONS EUS, a safe imaging procedure, is more accurate than ultrasonography and CT and may be as accurate as ERCP for diagnosing choledocholithiasis.

An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue.

The altered form of the high-mobility group A2 (HMGA2) gene is somehow related to the generation of human benign and malignant tumours of mesenchymal origin. However, only a few data on the expression of HMGA2 in malignant tumour originating from epithelial tissue are available. In this study, we examined the HMGA2 expression level in pancreatic carcinoma, and investigated whether alterations in the HMGA2 expression level are associated with a malignant phenotype in pancreatic tissue. High-mobility group A2 mRNA and protein expression was determined in eight surgically resected specimens of non-neoplastic tissue (six specimens of normal pancreatic tissue and two of chronic pancreatitis tissue) and 27 pancreatic carcinomas by highly sensitive reverse transcriptase–polymerase chain reaction (RT–PCR) techniques and immunohistochemical staining, respectively. Reverse transcriptase–polymerase chain reaction analysis revealed the expression of the HMGA2 gene in non-neoplastic pancreatic tissue, although its expression level was significantly lower than that in carcinoma. Immunohistochemical analysis indicated that the presence of the HMGA2 gene in non-neoplastic pancreatic tissue observed in RT–PCR reflects its abundant expression in islet cells, together with its focal expression in duct epithelial cells. Intense and multifocal or diffuse HMGA2 immunoreactivity was noted in all the pancreatic carcinoma examined. A strong correlation between HMGA2 overexpression and the diagnosis of carcinoma was statistically verified. Based on these findings, we propose that an increased expression level of the HMGA2 protein is closely associated with the malignant phenotype in the pancreatic exocrine system, and accordingly, HMGA2 could serve as a potential diagnostic molecular marker for distinguishing pancreatic malignant cells from non-neoplastic pancreatic exocrine cells.

Extrapancreatic neoplasms occur with unusual frequency in patients with intraductal papillary mucinous tumors of the pancreas

Objective:Intraductal papillary mucinous tumor (IPMT) of the pancreas has a favorable prognosis. Nonpancreatic primary neoplasms have potential prognostic significance in patients with IPMT. This study focused on the incidence and characteristics of nonpancreatic neoplasms in IPMT patients.Methods:Forty-two patients (mean age, 64 yr) with IPMT underwent surgery; 16 had adenoma and 26 adenocarcinoma. Preoperative and postoperative, nonpancreatic neoplasms were investigated. The mean postoperative follow-up period was 4.2 yr (range, 0.2–13 yr). Furthermore, 46 patients with pancreatic ductal adenocarcinoma were analyzed for nonpancreatic neoplasms.Results:Five-year survival rates were 100% for benign and 82% for malignant IPMT. Twenty patients (48%) had nonpancreatic neoplasms, before (n= 11), at (n= 4), and after (n= 10) surgery for IPMT. Fifteen patients (32%) had nonpancreatic malignancies. Nonpancreatic neoplasms included colorectal adenomas (21%) and adenocarcinomas (12%), and gastric carcinomas (10%). One patient died of subsequent bile duct carcinoma. Development of nonpancreatic neoplasms was related to age but not to gender, family history, adjuvant chemotherapy, or IPMT pathology. The incidences of nonpancreatic neoplasms and malignancies were significantly higher in patients with IPMT than in those with pancreatic ductal adenocarcinoma (11% and 7%, respectively).Conclusions:IPMT is associated with a high incidence of nonpancreatic neoplasms, particularly colorectal neoplasms. In IPMT patients, systemic surveillance may allow early detection of second tumors. In preoperative screening and postoperative follow-up of patients with nonpancreatic neoplasms, the possibility of IPMT should be considered.

Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria

Cholangiocarcinoma of the intrahepatic and extrahepatic bile ducts develops through a multistep histopathologic sequence. Premalignant or non-invasive neoplastic lesions of bile ducts have been historically called biliary dysplasia or atypical biliary epithelium. To this date, no standard terminology or classification system has been offered for these lesions. In 2005, a conceptual framework and diagnostic criteria for biliary intraepithelial neoplasia (BilIN) were proposed using the livers of patients with hepatolithiasis. We report herein an international interobserver agreement study on the diagnosis of biliary non-invasive neoplastic lesions with the goal to obtain a consensus on the terminology and grading. Seventeen pathologists from the United States, Europe and Asia participated in this study. They shared a digital file containing histological pictures of 30 foci of non-invasive neoplastic lesions selected from the biliary system of patients suffering from primary sclerosing cholangitis, choledochal cyst or hepatolithiasis. In the criteria, we proposed in 2005, BilIN was classified into three categories based on the degree of atypia: BilIN-1, BilIN-2 and BilIN-3. In this study, consensus was reached for the terminology of BilIN and the three-grade classification system. Interobserver agreement on the diagnosis was moderate (κ-value=0.45). On the basis of the suggestions and opinions obtained from the 17 participants, the original criteria for BilIN were revised. We now propose a new consensus classification of BilIN that may assist in allowing a more uniform terminology for the diagnosis of biliary non-invasive neoplastic lesions. This classification should help to advance clinical and research applications.

Two types of mucin-producing cystic tumors of the pancreas: diagnosis and treatment.

BACKGROUND This study focuses on clinicopathologic, imaging, and prognostic differences between two types of mucin-producing cystic tumors of the pancreas, with the aim of appropriate management of these tumors. METHODS Forty-six patients with mucin-producing cystic tumors underwent operation. The types of tumors were as follows: mucinous cystic neoplasm, adenoma (6) and adenocarcinoma (12); intraductal papillary tumor, adenoma (10) and adenocarcinoma (18). RESULTS Gender, age, symptoms, signs, tumor location and size, and the presence or absence of communication with the pancreatic duct differed between the two types. Mucinous cystadenocarcinomas showed deep invasion more often than intraductal papillary adenocarcinomas. Lymph node involvement was seen in 58% of mucinous cystadenocarcinomas but in only 22% of intraductal papillary adenocarcinomas. Tumors with mural nodules tended to show deep invasion and nodal metastasis. All four intraductal papillary tumors smaller than 3 cm without mural nodules were adenomas. Imaging studies allowed accurate differentiation between the two types but not between adenomas and adenocarcinomas. Five-year survival rates for patients with adenomas, mucinous cystadenocarcinomas, and intraductal papillary adenocarcinomas were 100%, 33%, and 81%, respectively. CONCLUSIONS Mucinous cystic neoplasm necessitates complete tumor excision with wide dissection of lymph nodes including paraaortic nodes. Intraductal papillary tumor requires only peripancreatic node dissection; for tumors smaller than 3 cm without mural nodules, node dissection may be unnecessary.

Matrilysin (MMP-7) as a significant determinant of malignant potential of early invasive colorectal carcinomas

Matrix metalloproteinases play a crucial role in tumour invasion and mestasis. Matrilysin (MMP-7) has been shown to correlate with nodal or distant metastasis in colorectal carcinomas; however, its implication in early invasive colorectal carcinomas has not been determined. This study was undertaken to clarify the association of matrilysin expression with clinicopathologic parameters in early invasive colorectal carcinomas. 38 early invasive colorectal carcinomas treated by local excision or radical surgery were examined. Tumour budding was evaluated as the number of dedifferentiation units along the entire invasive margin. Matrilysin protein levels were determined using immunohistochemical study. Univariate analysis showed that matrilysin expression alone was significantly associated with distant metastasis (P= 0.0339), and both tumour budding and matrilysin expression were significantly associated with adverse outcome (P= 0.0005, 0.0341). Histological differentiation, vessel invasion, and depth of invasion were not significantly associated with either distant metastasis or adverse outcome. Multivariate analysis confirmed that tumour budding and matrilysin expression were independently associated with adverse outcome, although the significance of matrilysin expression was marginal (P= 0.0488). Tumour budding at the invasive margin and matrilysin expression are more useful in identifying high-risk groups for adverse outcome in patients with early invasive colorectal carcinomas.

Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker

The emphasis in anticancer drug discovery has always been on finding a drug with great antitumor potential but few side‐effects. This can be achieved if the drug is specific for a molecular site found only in tumor cells. Here, we find the enhancer of zeste homolog 2 (EZH2) to be highly overexpressed in lung and other cancers, and show that EZH2 is integral to proliferation in cancer cells. Quantitative real‐time PCR analysis revealed higher expression of EZH2 in clinical bladder cancer tissues than in corresponding non‐neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpress EZH2, using cDNA microarray analysis. Immunohistochemical analysis showed positive staining for EZH2 in 14 of 29 cases of bladder cancer, 135 of 292 cases of non‐small‐cell lung cancer (NSCLC), and 214 of 245 cases of colorectal cancer, whereas no significant staining was observed in various normal tissues. We found elevated expression of EZH2 to be associated with poor prognosis for patients with NSCLC (P = 0.0239). In lung and bladder cancer cells overexpressing EZH2, suppression of EZH2 using specific siRNAs inhibited incorporation of BrdU and resulted in significant suppression of cell growth, even though no significant effect was observed in the normal cell strain CCD‐18Co, which has undetectable EZH2. Because EZH2 expression was scarcely detectable in all normal tissues we examined, EZH2 shows promise as a tumor‐specific therapeutic target. Furthermore, as elevated levels of EZH2 are associated with poor prognosis of patients with NSCLC, its overexpression in resected specimens could prove a useful molecular marker, indicating the necessity for a more extensive follow‐up in some lung cancer patients after surgical treatment. (Cancer Sci 2011; 102: 1298–1305)