- Email: [email protected]
Su1497 Do the Updated Sendai Guidelines Improve Diagnosis of Advanced Neoplasia in Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) of the Pancreas?
AGA Abstracts
papillary mucinous neoplasm and to assess the impact on the diagnosis of IPMN. Methods: We retrospectively analysed the clinicopathological factors of 177 patients (114 men, median age 63 yr) undergoing resection for branch duct type IPMNs at 15 tertiary hospitals in korea that had the diameter of main pancreatic duct less than 5 mm for identifying malignant predictors of this neoplasm. For the analysis, Br-IPMN with adenoma (n=72), borderline neoplasm (n=66) were grouped as benign and Br-IPMNs with carcinoma in situ(n=10), and invasive carcinoma (n=29) as malignant. Malignant IPMNs were defined as those with noninvasive (n=10 noninvasive carcinoma, and 29 invasive carcinoma). and invasive IPMN. Results: Among 177 patients with branch duct IPMN, we found significant predictors for malignancy in these patients in a univariate analysis; cyst size > 3cm, presence of a mural nodule in the cyst at abdominal CT, the history of acute pancreatitis, serum CA19-9. In a multivariate analysis among 177 patients, a mural nodule on CT imaging, cyst size>3cm, and serum CA19-9 were independent factors associated with malignancy. In patients (n= 110) who had endoscopic ultrasonography (EUS), cyst size > 3cm (odd ratio=10.6, CI= 2.812-40.199) and mural nodule larger than 5mm (odd ratio=14.9, CI=4.027-55.418) on EUS imaging is strongly associated with Malignant Br-IPMNs (p<0.001). The area under the curve for the mural nodule size of malignant predictors for branch duct IPMNs (0.855) was higher than cyst size (0.772). When the mural nodule size > 5mm used instead of definitive mural nodule on EUS imaging in the 2012 international consensus guideline for IPMNs, the sensitivity and specificity was 84% and 85%. Conclusions: We identified useful predictive factors for malignancy in pure branch duct IPMN ; the presence of mural nodule and cyst size > 3cm on abdominal CT imaging, and the mural nodule larger than 5 mm on EUS imaging. In the worrisome features of 2012 international guideline for surgical indication of IPMNs, using the mural nodule larger than 5 mm instead of definitive mural nodule on EUS imaging may be reasonable.
Su1496 Evaluation of Chromosomal Abnormalities by Fluorescence in Situ Hybridization in Intraductal Papillary Mucinous Neoplasm Katsuyuki Miyabe, Yasuki Hori, Takahiro Nakazawa, Kazuki Hayashi, Itaru Naitoh, Shuya Shimizu, Hiromu Kondo, Michihiro Yoshida, Hiroaki Yamashita, Shuichiro Umemura, Akihisa Kato, Hirotaka Ohara, Takashi Joh, Hiroshi Inagaki BACKGROUND: Diagnosis of pancreatic malignancy on cytological specimen by fluorescence in situ hybridization (FISH) has been recently reported; however, few studies of chromosomal abnormalities between intraductal papillary mucinous neoplasm (IPMN) using FISH have been reported so far. The aim of this study is to examine the difference of chromosomal and locus abnormalities in IPMN. METHODS: Twenty-eight cases of nonmalignant IPMN (8 cases of low grade dysplasia, 9 of intermediate grade dysplasia, 2 of high grade dysplasia), 11 cases of IPMN with an associated invasive carcinoma (IPMC), and 18 cases of normal pancreatic ductal epithelial cells on the resected specimens were studied. IPMN cases were histologically classified into gastric type (n=18), intestinal type (n=8), pancreatobiliary type (n=1), and oncyic type (n=1). FISH analysis was performed to detect aneuploidies of chromosome (3, 6, 7, 8, 17, and 18) and losses of gene (p16 at 9p21 and p53 at 17p13). We evaluated chromosome (monosomy and polysomy) and locus (hemizygous deletion and homozygous deletion) abnormalities by the comparison between non-malignant IPMN and normal epithelium, among the degree of dysplasia or histological type in IPMN, and between the adenomatous and cancerous epithelium on IPMC. RESULTS: Polysomy 6 were significantly more frequent in non-malignant IPMN than in normal epithelium (4/ 17 vs 0/18, p=0.0455). Polysomy 18 and p53 hemizygous deletion were significantly more frequent in IPMC than in non-malignant IPMN (polysomy 18, 5/11 vs 1/17, p=0.00221; p53, 7/11 vs 0/17, p<0.0001). The mean polysomy number was significantly more in IPMC than in non-malignant IPMN (1.72 vs 0.71, p=0.0423). Any kinds of monosomies or the mean monosomy number did not differ significantly between non-malignant IPMN and IPMC. All p53 deletion in IPMC were hemizygous deletion (9/9, 100%). No significance was shown in the study of the chromosome and gene abnormalities of IPMN between low and intermediate grade dysplasia, and between gastric and intestinal type. The mean polysomy number also did not differ significantly between low and intermediate grade dysplasia (0 vs 0.75). Polysomy 6, 18, and p53 hemizygous deletion had same results even in the comparison between the adenomatous epithelium of IPMC and normal epithelium (3/11 vs 0/18, p=0.0452), and between malignant and adenomatous epithelium (polysomy 18, 5/11 vs 0/11, p=0.0351; p53 hemizygous deletion, 7/11 vs 2/11, p=0.0440). CONCLUSION:Our study indicates that polysomy 6 play important role in the adenomatous change from pancreas epithelium, as well as the role of polysomy 18 and p53 deletion in the malignant change from non-malignant IPMN.
Su1495 Proteomic Studies on Aspirates From Cystic Neoplasms of the Pancreas Provide New Clues to Their Molecular Background and Reveal Novel Biomarker Candidates Karolina S. Jabbar, Caroline S. Verbeke, Björn Lindkvist, Gunnar C. Hansson, Riadh Sadik Introduction In recent years, IPMN and MCN have been identified as precursors of pancreatic cancer. However, our understanding of the molecular backgrounds of these tumors is still incomplete, and their diagnosis remains challenging. We performed a systematic proteomic analysis of aspirates from different pancreatic cystic neoplasms to further elucidate their pathogenesis and identify new biomarker candidates Methods Aspirates from 24 patients with pancreatic cystic lesions (15 females, median age 63), obtained through EUS-FNA were used for the analysis. Samples were selected to represent triplicates of the most common cystic tumors: serous cystic tumors, MCN, cystic ductal adenocarcinomas, and IPMN of gastric, intestinal and pancreatobiliary type. For comparison, six pseudocysts were included. Nine samples were characterized as intrinsically benign, five as premalignant and ten as malignant (minimum high-grade dysplasia). Histology was procurable in 20/24 cases (83%), including 17/18 (94%) cystic tumors. Pseudocysts were, in the absence of histology, identified by their spontaneous regression/resolution. Samples were prepared by the filter aided sample preparation (FASP) method (modified) and digested by trypsin, before analysis by nano-LC MS/MS on a Q-Exactive instrument. Data were searched against the UniProt/Swissprot database, using the Andromeda search engine integrated in MaxQuant. Pathway analyses were performed by Ingenuity Pathway Analysis (IPA). Results A total of 1385 proteins were identified. After filtering out single occurrences, 541 proteins were found to be unique to pre-/malignant, and 273 to malignant neoplasms. The greatest degree of similarity was observed for IPMN and ductal adenocarcinomas: all protein identifications from the latter, except two, were shared with IPMN. Pathway analysis revealed the transcription factors XBP1 (involved in ER stress response) and NFE2L2 (defense against oxidative stress) as prominent upstream regulators for proteins differentially expressed in pre-/malignant tumors (i.e., MCN, IPMN and ductal adenocarcinoma). PI3K/AKT and ERK5 were central components of the molecular networks generated for these tumors. Dysregulation of p53 and KRAS were (as previously described) identified as major events in malignant transformation. Notable predicted upstream regulators by tumor type were: TGFβ for serous cystic tumors, c-MYC for MCN, and IL1B and tretinoin for IPMN. Furthermore, the study identified several novel biomarker candidates (Table 1). Conclusions This proteomic study has tentatively identified molecular pathways/events that have not been described previously in the context of MCN and IPMN. Moreover, several new biomarker candidates have been selected for further study. Targeted quantitative proteomic studies to define cut-offs and validate these markers are ongoing. Table 1
AGA Abstracts
Su1497 Do the Updated Sendai Guidelines Improve Diagnosis of Advanced Neoplasia in Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) of the Pancreas? Pavlos Z. Kaimakliotis, Aaron J. Small, Vinay Chandrasekhara, Gregory G. Ginsberg, Michael L. Kochman, Nuzhat A. Ahmad Background: The 2006 Sendai consensus guidelines for management of mucinous pancreatic cysts had high sensitivity, but low specificity. The guidelines were updated in 2012. Whether the updated guidelines improve specificity is unknown. Aims: To determine whether application of the 2012 Sendai guidelines increases specificity for identification of advanced neoplasia in suspected IPMN and MCN. Methods: The study was a single center, retrospective analysis using a database of patients with cystic lesions of the pancreas who underwent resection between 2000 and 2008. Patient age, gender, clinical presentation, cross sectional imaging, endoscopic ultrasound (EUS) and pathology at the time of surgery were analyzed. The 2006 Sendai guidelines were applied to determine the sensitivity and specificity for detecting advanced neoplasia in suspected branch duct IPMN (IPMN-Br) and MCN of the pancreas. Advanced neoplasia is defined as carcinoma or high grade dysplasia on final surgical pathology. Indications for resection of IPMN-Br and MCN include at least one of the following criteria: main pancreatic duct ≥ 10mm, cyst size ≥ 30mm, intramural nodules, cyst fluid cytology suspicious/positive for malignancy. The revised 2012 Sendai guidelines were then applied to determine the change in sensitivity and specificity for detecting advanced neoplasia. Results: A total of 92 patients (60 women; median age 55.5 years; age range 20 to 83 years) underwent resection for presumed cystic neoplasms at our institution during the study period. Advanced neoplasia was found in 12 patients (8 adenocarcinoma, 4 high grade dysplasia); 9 patients had MCN and 3 patients had unsuspected main duct IPMN. Cyst size was ≥ 30mm in 9 patients with advanced neoplasia. Non-advanced neoplasia was found in 70 patients (28 MCN, 4 main duct IPMN, 6 IPMN-Br, 16 pseudocysts, 11 serous cystadenomas, 8 neuroendocrine tumors, 4 lymphoepithelial cysts and 3 other benign cystic lesions of the pancreas). Application of the 2006 Sendai guidelines results in a sensitivity for advanced neoplasia of 91.7% and a specificity of 23.8%. There was 1 patient with HGD missed with the 2006 Sendai guidelines; cyst size <30mm and no other high risk stigmata on imaging. Application of the revised 2012 Sendai guidelines results in a decrease in sensitivity 75% (p=0.3) and an increase in specificity to 43.8% (p=0.007). There were 3 patients with HGD missed with the revised 2012 Sendai guidelines; 2 with cyst size ≥ 30mm, 1 with cyst size < 30mm, and no other high risk or worrisome features present. Conclusion: The updated 2012 Sendai criteria are more specific but less sensitive in the detection of advanced neoplasia in mucinous cystic neoplasms. Using the current Sendai guidelines mucinous pancreatic cysts with HGD may be missed.
S-484
papillary mucinous neoplasm and to assess the impact on the diagnosis of IPMN. Methods: We retrospectively analysed the clinicopathological factors of 177 patients (114 men, median age 63 yr) undergoing resection for branch duct type IPMNs at 15 tertiary hospitals in korea that had the diameter of main pancreatic duct less than 5 mm for identifying malignant predictors of this neoplasm. For the analysis, Br-IPMN with adenoma (n=72), borderline neoplasm (n=66) were grouped as benign and Br-IPMNs with carcinoma in situ(n=10), and invasive carcinoma (n=29) as malignant. Malignant IPMNs were defined as those with noninvasive (n=10 noninvasive carcinoma, and 29 invasive carcinoma). and invasive IPMN. Results: Among 177 patients with branch duct IPMN, we found significant predictors for malignancy in these patients in a univariate analysis; cyst size > 3cm, presence of a mural nodule in the cyst at abdominal CT, the history of acute pancreatitis, serum CA19-9. In a multivariate analysis among 177 patients, a mural nodule on CT imaging, cyst size>3cm, and serum CA19-9 were independent factors associated with malignancy. In patients (n= 110) who had endoscopic ultrasonography (EUS), cyst size > 3cm (odd ratio=10.6, CI= 2.812-40.199) and mural nodule larger than 5mm (odd ratio=14.9, CI=4.027-55.418) on EUS imaging is strongly associated with Malignant Br-IPMNs (p<0.001). The area under the curve for the mural nodule size of malignant predictors for branch duct IPMNs (0.855) was higher than cyst size (0.772). When the mural nodule size > 5mm used instead of definitive mural nodule on EUS imaging in the 2012 international consensus guideline for IPMNs, the sensitivity and specificity was 84% and 85%. Conclusions: We identified useful predictive factors for malignancy in pure branch duct IPMN ; the presence of mural nodule and cyst size > 3cm on abdominal CT imaging, and the mural nodule larger than 5 mm on EUS imaging. In the worrisome features of 2012 international guideline for surgical indication of IPMNs, using the mural nodule larger than 5 mm instead of definitive mural nodule on EUS imaging may be reasonable.
Su1496 Evaluation of Chromosomal Abnormalities by Fluorescence in Situ Hybridization in Intraductal Papillary Mucinous Neoplasm Katsuyuki Miyabe, Yasuki Hori, Takahiro Nakazawa, Kazuki Hayashi, Itaru Naitoh, Shuya Shimizu, Hiromu Kondo, Michihiro Yoshida, Hiroaki Yamashita, Shuichiro Umemura, Akihisa Kato, Hirotaka Ohara, Takashi Joh, Hiroshi Inagaki BACKGROUND: Diagnosis of pancreatic malignancy on cytological specimen by fluorescence in situ hybridization (FISH) has been recently reported; however, few studies of chromosomal abnormalities between intraductal papillary mucinous neoplasm (IPMN) using FISH have been reported so far. The aim of this study is to examine the difference of chromosomal and locus abnormalities in IPMN. METHODS: Twenty-eight cases of nonmalignant IPMN (8 cases of low grade dysplasia, 9 of intermediate grade dysplasia, 2 of high grade dysplasia), 11 cases of IPMN with an associated invasive carcinoma (IPMC), and 18 cases of normal pancreatic ductal epithelial cells on the resected specimens were studied. IPMN cases were histologically classified into gastric type (n=18), intestinal type (n=8), pancreatobiliary type (n=1), and oncyic type (n=1). FISH analysis was performed to detect aneuploidies of chromosome (3, 6, 7, 8, 17, and 18) and losses of gene (p16 at 9p21 and p53 at 17p13). We evaluated chromosome (monosomy and polysomy) and locus (hemizygous deletion and homozygous deletion) abnormalities by the comparison between non-malignant IPMN and normal epithelium, among the degree of dysplasia or histological type in IPMN, and between the adenomatous and cancerous epithelium on IPMC. RESULTS: Polysomy 6 were significantly more frequent in non-malignant IPMN than in normal epithelium (4/ 17 vs 0/18, p=0.0455). Polysomy 18 and p53 hemizygous deletion were significantly more frequent in IPMC than in non-malignant IPMN (polysomy 18, 5/11 vs 1/17, p=0.00221; p53, 7/11 vs 0/17, p<0.0001). The mean polysomy number was significantly more in IPMC than in non-malignant IPMN (1.72 vs 0.71, p=0.0423). Any kinds of monosomies or the mean monosomy number did not differ significantly between non-malignant IPMN and IPMC. All p53 deletion in IPMC were hemizygous deletion (9/9, 100%). No significance was shown in the study of the chromosome and gene abnormalities of IPMN between low and intermediate grade dysplasia, and between gastric and intestinal type. The mean polysomy number also did not differ significantly between low and intermediate grade dysplasia (0 vs 0.75). Polysomy 6, 18, and p53 hemizygous deletion had same results even in the comparison between the adenomatous epithelium of IPMC and normal epithelium (3/11 vs 0/18, p=0.0452), and between malignant and adenomatous epithelium (polysomy 18, 5/11 vs 0/11, p=0.0351; p53 hemizygous deletion, 7/11 vs 2/11, p=0.0440). CONCLUSION:Our study indicates that polysomy 6 play important role in the adenomatous change from pancreas epithelium, as well as the role of polysomy 18 and p53 deletion in the malignant change from non-malignant IPMN.
Su1495 Proteomic Studies on Aspirates From Cystic Neoplasms of the Pancreas Provide New Clues to Their Molecular Background and Reveal Novel Biomarker Candidates Karolina S. Jabbar, Caroline S. Verbeke, Björn Lindkvist, Gunnar C. Hansson, Riadh Sadik Introduction In recent years, IPMN and MCN have been identified as precursors of pancreatic cancer. However, our understanding of the molecular backgrounds of these tumors is still incomplete, and their diagnosis remains challenging. We performed a systematic proteomic analysis of aspirates from different pancreatic cystic neoplasms to further elucidate their pathogenesis and identify new biomarker candidates Methods Aspirates from 24 patients with pancreatic cystic lesions (15 females, median age 63), obtained through EUS-FNA were used for the analysis. Samples were selected to represent triplicates of the most common cystic tumors: serous cystic tumors, MCN, cystic ductal adenocarcinomas, and IPMN of gastric, intestinal and pancreatobiliary type. For comparison, six pseudocysts were included. Nine samples were characterized as intrinsically benign, five as premalignant and ten as malignant (minimum high-grade dysplasia). Histology was procurable in 20/24 cases (83%), including 17/18 (94%) cystic tumors. Pseudocysts were, in the absence of histology, identified by their spontaneous regression/resolution. Samples were prepared by the filter aided sample preparation (FASP) method (modified) and digested by trypsin, before analysis by nano-LC MS/MS on a Q-Exactive instrument. Data were searched against the UniProt/Swissprot database, using the Andromeda search engine integrated in MaxQuant. Pathway analyses were performed by Ingenuity Pathway Analysis (IPA). Results A total of 1385 proteins were identified. After filtering out single occurrences, 541 proteins were found to be unique to pre-/malignant, and 273 to malignant neoplasms. The greatest degree of similarity was observed for IPMN and ductal adenocarcinomas: all protein identifications from the latter, except two, were shared with IPMN. Pathway analysis revealed the transcription factors XBP1 (involved in ER stress response) and NFE2L2 (defense against oxidative stress) as prominent upstream regulators for proteins differentially expressed in pre-/malignant tumors (i.e., MCN, IPMN and ductal adenocarcinoma). PI3K/AKT and ERK5 were central components of the molecular networks generated for these tumors. Dysregulation of p53 and KRAS were (as previously described) identified as major events in malignant transformation. Notable predicted upstream regulators by tumor type were: TGFβ for serous cystic tumors, c-MYC for MCN, and IL1B and tretinoin for IPMN. Furthermore, the study identified several novel biomarker candidates (Table 1). Conclusions This proteomic study has tentatively identified molecular pathways/events that have not been described previously in the context of MCN and IPMN. Moreover, several new biomarker candidates have been selected for further study. Targeted quantitative proteomic studies to define cut-offs and validate these markers are ongoing. Table 1
AGA Abstracts
Su1497 Do the Updated Sendai Guidelines Improve Diagnosis of Advanced Neoplasia in Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) of the Pancreas? Pavlos Z. Kaimakliotis, Aaron J. Small, Vinay Chandrasekhara, Gregory G. Ginsberg, Michael L. Kochman, Nuzhat A. Ahmad Background: The 2006 Sendai consensus guidelines for management of mucinous pancreatic cysts had high sensitivity, but low specificity. The guidelines were updated in 2012. Whether the updated guidelines improve specificity is unknown. Aims: To determine whether application of the 2012 Sendai guidelines increases specificity for identification of advanced neoplasia in suspected IPMN and MCN. Methods: The study was a single center, retrospective analysis using a database of patients with cystic lesions of the pancreas who underwent resection between 2000 and 2008. Patient age, gender, clinical presentation, cross sectional imaging, endoscopic ultrasound (EUS) and pathology at the time of surgery were analyzed. The 2006 Sendai guidelines were applied to determine the sensitivity and specificity for detecting advanced neoplasia in suspected branch duct IPMN (IPMN-Br) and MCN of the pancreas. Advanced neoplasia is defined as carcinoma or high grade dysplasia on final surgical pathology. Indications for resection of IPMN-Br and MCN include at least one of the following criteria: main pancreatic duct ≥ 10mm, cyst size ≥ 30mm, intramural nodules, cyst fluid cytology suspicious/positive for malignancy. The revised 2012 Sendai guidelines were then applied to determine the change in sensitivity and specificity for detecting advanced neoplasia. Results: A total of 92 patients (60 women; median age 55.5 years; age range 20 to 83 years) underwent resection for presumed cystic neoplasms at our institution during the study period. Advanced neoplasia was found in 12 patients (8 adenocarcinoma, 4 high grade dysplasia); 9 patients had MCN and 3 patients had unsuspected main duct IPMN. Cyst size was ≥ 30mm in 9 patients with advanced neoplasia. Non-advanced neoplasia was found in 70 patients (28 MCN, 4 main duct IPMN, 6 IPMN-Br, 16 pseudocysts, 11 serous cystadenomas, 8 neuroendocrine tumors, 4 lymphoepithelial cysts and 3 other benign cystic lesions of the pancreas). Application of the 2006 Sendai guidelines results in a sensitivity for advanced neoplasia of 91.7% and a specificity of 23.8%. There was 1 patient with HGD missed with the 2006 Sendai guidelines; cyst size <30mm and no other high risk stigmata on imaging. Application of the revised 2012 Sendai guidelines results in a decrease in sensitivity 75% (p=0.3) and an increase in specificity to 43.8% (p=0.007). There were 3 patients with HGD missed with the revised 2012 Sendai guidelines; 2 with cyst size ≥ 30mm, 1 with cyst size < 30mm, and no other high risk or worrisome features present. Conclusion: The updated 2012 Sendai criteria are more specific but less sensitive in the detection of advanced neoplasia in mucinous cystic neoplasms. Using the current Sendai guidelines mucinous pancreatic cysts with HGD may be missed.
S-484