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W1410 Risk of Pancreatic Ductal Adenocarcinomas in Long-Term Followed-Up Patients with Branch Duct Intraductal Papillary-Mucinous Neoplasms
AGA Abstracts
PETs. Reproducibility is better for MIB-1 proliferation index and SST2 expression than for microvascular density. Sampling variability should be taken into consideration as a potential limitation to the assessment of prognostic and therapeutic markers in biopsy samples from metastatic PETs.
W1408 Senescence in Intraductal Papillary Mucinous Neoplasms of the Pancreas Yoshihiro Miyasaka, Eishi Nagai, Kenoki Ohuchida, Kohei Nakata, Akifumi Hayashi, Kazuhiro Mizumoto, Koji Yamaguchi, Masazumi Tsuneyoshi, Masao Tanaka Background/Aim: Senescence is a stable arrest of cell proliferation which was originally reported in cultured human fibroblasts through a finite number of passages. Recent studies reported that senescence was observed in neoplasms, especially in premalignant lesions, and played a role as a barrier against malignant progression. Previously, we reported that DNA damage checkpoint activation, which is considered to induce senescence in premalignant lesion, was observed in the early stage of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and diminished in the malignant IPMNs. In the current study, we analyzed several senescence markers, including senescence-associated beta-galactosidase (SA betagal) expression, formation of senescence-associated heterochromatin foci (SAHF) and p16 expression in IPMNs with different grades of dysplasia (adenoma, borderline, carcinoma in situ and invasive carcinoma) to verify senescence in IPMNs. Materials and Methods: Frozen sections from 33 IPMN patients (15 adenoma, 4 borderline, 10 carcinoma in situ, and 4 invasive carcinoma) were subjected to the analysis of SA beta-gal expression and immunofluorescence of HP1-gamma, which is a marker of SAHF. Formalin-fixed paraffin embedded sections from 117 IPMN patients (46 adenoma, 26 borderline, 21 carcinoma in situ, and 24 invasive carcinoma) were subjected to immunohistochemical staining of p16. Result: The positive rate of SA beta-gal expression is the highest in adenoma and gradually decreases according to the progression of dysplasia (80% of adenoma, 75% of borderline, 50% of carcinoma in situ, and 25% of invasive carcinoma). Most of the SA beta-gal expressing lesions also displayed SAHF formation. Expression of p16 showed similar tendency to the other two markers: 89% of adenoma, 80% of borderline, 67% of carcinoma in situ, and 46% of invasive carcinoma were positive for p16 staining. Conclusion: Senescence is induced in the early stage of IPMNs and gradually attenuated according to the progression of dysplasia, suggesting that senescence plays a significant role in preventing the tumor progression and its attenuation allows the malignant transformation of IPMNs.
W1406 Risk Factors for Pancreatic Endocrine Tumors: Multicentre Case-Control Study Gabriele Capurso, Massimo Falconi, Francesco Panzuto, Maria Rinzivillo, Rossella Bettini, Michela Di Fonzo, Letizia Boninsegna, Sara Cassetta, Vito D. Corleto, Paolo Pederzoli, Gianfranco Delle Fave Context: Pancreatic endocrine tumors (PETs) are rare neoplasms with an incidence of 0,1/ 100000. Apart from genetic disorders, risk factors for their occurrence have never been investigated. Smoking, drinking and obesity have been found to be risk factors for GI carcinoids and pancreatic ductal adenocarcinoma (PDAC). The possible role of family history has not been evaluated in GI endocrine tumors before. Aim: to determine risk factors for the occurrence of PETs. Methods: Multicentre C-C study. Patients with either new diagnosis of sporadic PET or in follow-up seen during a 12-month period were administered a questionnaire registering data on smoking, alcohol intake, BMI 1 year before PET diagnosis, and family history of cancer. Controls were patients with non-neoplastic, non-chronic disorders. Fisher test and wilcoxon test were used as appropriate. Univariate and multivariate analysis were performed by using a logistic regression model. Results: 146 patients (50% F) and 275 controls (52% F) enrolled. Mean age 52,5 for PETs and 53,8 for controls. 39,6% of PETs and 30,3% of controls were smokers (p=0.07). A pack x year (no.of daily packs x years of smoking)>20 more frequent amongst PETs (21% vs 15,4%; p=0.03). Drinking more frequent in PETs (35,3%) than controls (23,1%) (p=0.01). The median BMI was 24 (1740) in PETs and 25 (17-38) in controls (p=0.178), with obesity similarly distributed (9,7% vs 10,2%). 54,5% of PETS had at least one 1st degree family member with a neoplasm vs 36,4% of controls (p=0.0004). 15.9% of PETs had >2 1st degree family members with a neoplasm vs 5,1% of controls (p=0.0004). 33,1% of PETs and 10,5% controls had both 1st and 2nd degree cancer family history (p<0.000001). PDAC 1st or 2nd degree family history was found in 7,5% of PETs and 1.8% of controls (p=0.009). All 7 PETs with PDAC 1st degree family history were NF. No other site specific neoplasm family history significantly different. At a univariate analysis, drinking (OR 1,13 per increase in alcohol unit), 1st degree family history of any cancer (OR 2,06), 1st+2nd degree cancer family history (OR 4,1), PDAC 1st degree family history (OR 6,8) and PDAC 1st or 2nd degree family history (OR 4,3) were significant risk factors, with only 1st degree family history of any cancer (OR 1,7) and 1st or 2nd degree family history of PDAC (OR 3,2) significant by multivariate analysis. Conclusions: family history of cancer, particularly of PDAC, seem risk factors for PETs. This last finding is interesting as PETs occur also in families with familial PDAC. Smoking and drinking seem to show a trend toward an increased risk.
W1409 The Incidence of Other Malignancies in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas: Emphasis On Whole-Body Surveillance Ikuya Miki, Hiromu Kutsumi, Tetsuo Ajiki, Ippei Matsumoto, Shiei Yoshida, Yoshinori Morita, Takashi Toyonaga, Masaru Yoshida, Hideto Inokuchi, Shigeto Mizuno, Takeshi Azuma Background: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are believed to progress slowly showing a spectrum of neoplastic transformations, which are characterized by a favorable prognosis. Therefore, other malignancies may have a potential significance for prognosis in patients with IPMNs. Aims: In order to determine an appropriate surveillance strategy of extrapancreatic cancers, we examined the incidence and characteristics of preexisting, coexisting and subsequent malignancies in patients with IPMNs in Japan. Methods: Medical records were reviewed retrospectively in patients with IPMNs treated in Kobe University Hospital during 1990-2007. History of a prediagnostic, a concurrent, or a postdiagnostic development of an extrapancreatic neoplasm was investigated thoroughly. IPMNs were diagnosed by multiple radiographic modalities including abdominal ultrasonography, computed tomography, magnetic resonance cholangio-pancratography, and endoscopic retrograde pancreatography. Results: One hundred four patients were diagnosed as IPMNs (male: female=66:38, mean age; 64.5±8.2 years). Postdiagnostic follow-up period was 6.3±3.9 years (range, 0.2-12 years). Of these, 47 showed main duct type and 57 branched type. Eighty-two patients underwent surgery, and histological diagnosis was confirmed. Of 104 patients with IPMNs, 31 (29.7%) developed 36 extrapancreatic malignancies, which were found before (n = 18), at (n = 12) and after (n = 6) the diagnosis of IPMNs. Major associated malignancies were gastric cancer (n = 17), pulmonary cancer (n = 4), urological cancer (n= 4), breast cancer (n=4), colorectal cancer (n = 3), laryngeal cancer (n=1), cervical cancer (n=1), biliary tract cancer (n=1) and thyroid cancer (n=1). Extrapancreatic malignancies were sometimes detected by PET. Comparisons of the clinicopathological features in IPMNs with and without other malignancies revealed no significant differences in age, sex, location of the pancreas, type of IPMNs, or histological findings of IPMNs. Conclusion: IPMNs are associated with a high incidence of variable extrapancreatic neoplasms regardless of clinicopathological features, and a special notice is that one third patients with IPMNs would develop other malignancies. At the diagnosis of IPMNs, systemic surveillance, at least esophagogastroscopy, colonoscopy, mammography and chest CT, should be considered in order to detect second tumors. If possible, consultation with urology and gynecology is also needed. PET will be one of the most useful surveillance modalities in the future.
W1407 Regiv Expression Is Involved in ‘Intestinal Type' Carcinogenesis of Intraductal Papillary Mucinous Neoplasm of the Pancreas Kohei Nakata, Eishi Nagai, Kenoki Ohuchida, Yoshihiro Miyasaka, Akifumi Hayashi, Kazuhiro Mizumoto, Masazumi Tsuneyoshi, Masao Tanaka Background/Aims: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas show broad spectrum of dysplasia ranging from adenoma to carcinoma. Recently, IPMN is subclassified into 4 types including gastric, intestinal, oncocytic, and pancreatobiliary (PB)-types based on histological phenotypes. PB-type and intestinal-type IPMNs have been reported to associated with tubular invasion and mucinous invasion, respectively. Regenerating gene (REG) IV is secreted protein and dysregulation of RegIV expression is associated with an early step of the adenoma-carcinoma sequence. In the present study, we investigated the RegIV expression in a large cohort of patients with IPMNs, focusing on both the grade of atypia and histological subtypes. Materials and Methods: IPMNs were analyzed by imunohistochemical staining of RegIV. The lesions were classified as adenoma (IPMA), borderline (IPMB) and carcinoma (IPMC) on the basis of dysplasia, and also subdivided into four groups based on histological phenotype. Results: Of 127 IPMNs, 64 (54%) were subclassified as gastric-type, 38 (30%) as intestinal-type, eight (7%) as PB-type, three (2%) as oncocytictype, and eight (7%) as unclassified type. All of the invasive components in the gastric-, PB-, oncocytic- and unclassified neoplasms (6, 7, 1 and 3 IPMNs, respectively) displayed a tubular invasive pattern, whereas five of six (83%) intestinal-type IPMNs and two of five (40%) unclassified-type IPMNs with invasive components showed a mucinous noncystic pattern. Intestinal-, PB- and unclassified type IPMNs showed significantly high grade of atypia compared with gastric-type IPMNs (P<0.05). Of 126 IPMNs, 59 (46%) demonstrated positive staining of RegIV. The positive rate of RegIV of intestinal-, gastric-, PB- , oncocyticand unclassified IPMNs were 38/38 (100%), 18/68 (26%), 0/8 (0%), 0/ 3 (0%) and 3/8 (38%), respectively. Compared with IPMA (18/52, 35%), RegIV expression was observed more frequently in borderline IPMB (19/28, 68%) and IPMC (22/45, 48%). In analyses of IPMC cases, RegIV expression was observed more frequently in intestinal-type (18/18, 100%) than in PB- (0/8, 0%), oncocytic- (0/3. 0%), gastric- (1/8, 16%) and unclassified type (3/ 8, 38%). Five of seven (86%) mucinous invasive carcinomas showed positive Reg IV expression, while only one (6%) of 17 tubular invasive carcinomas did so. Conclusion: Reg IV expression was found more frequently in intestinal type IPMN including mucinous carcinoma than in the other types of IPMN including tubular invasive carcinoma, suggesting that RegIV might be involved in ‘intestinal type' carcinogenesis of IPMN of the pancreas.
AGA Abstracts
W1410 Risk of Pancreatic Ductal Adenocarcinomas in Long-Term Followed-Up Patients with Branch Duct Intraductal Papillary-Mucinous Neoplasms Satoshi Tanno, Tomoya Nishikawa, Kazuya Koizumi, Junpei Sasajima, Kazumasa Nakamura, Yusuke Mizukami, Toshikatsu Okumura, Yutaka Kohgo Background: Although branch duct type intraductal papillary-mucinous neoplasms (BrIPMNs) are reported to be slow-growing tumors with a favorable prognosis, the risk of pancreatic ductal adenocarcinomas apart from branch duct lesions in patients with Br-IPMNs is unknown. Objective: The aim of this study was to elucidate the incidence and risk of pancreatic ductal adenocarcinomas in long-term followed-up patients with Br-IPMNs. Methods: We studied a prospective and single center cohort of 89 consecutive patients (56 (62.9%) men, median age 68 years) with Br-IPMNs and a follow-up of at least two years (median follow-up 64 months; range 24-158) in order to exclude other cystic neoplasms or pseudocysts. We calculated the age and sex standardized incidence ratio (SIR) as the ratio as provided by Japanese Journal of Health and Welfare Statistics. Results: Four cases of pancreatic ductal adenocarcinomas (4.5% of patients) distant from Br-IPMN in the same pancreas were observed in 552 patients years of follow-up (7.2 per 1,000 patient years).
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using a differential proteomic technique; 2 - to identify proteins associated to malignant IPMN transformation, thus constituting specific biomarkers. Material and Methods: 43 mucus samples were obtained from surgically-resected IPMN in 43pts. IPMN were benign (lowand moderate-grade dysplasia) and malignant (high-grade dysplasia and invasive adenocarcinoma) in 21 and 22 pts, respectively. After protein extraction and quantitative assessment, mass spectrometry SELDI-TOF (Surface Enhanced Laser Desorption Ionisation-Time-OfFlight) was used to determine protein expression profiles in IPMN mucus. Protein peaks that significantly differed between benign and malignant IPMN (AUC > 0.88, p<10-4 with high intensity) were identified using Ciphergen express software and compared. Results : Among 952 protein peaks identified by SELDI-TOF, 31 were differentially expressed in benign and malignant IPMN (p <0.001). Among them, 5 proteins of interest were selected due to high diagnostic accuracy and ability to distinguish between the 2 groups of tumors. Proteic weights (m/z) were 5217, 6326, 6719, 10453 and 10849 Da, respectively. There was no correlation between protein expression and IPMN type (branch-duct, main-duct, combined). Conclusion : Multistep carcinogenic process in IPMN is associated with differential protein expression that can be identified in the mucus secreted by tumoral epithelium. Mass spectrometry allows to characterize proteins that could be associated with malignant transformation. Proteins identification is on progress.
W1411 In Situ Detection of Vhl/HIF Pathway Proteins Identifies a Pancreatic Endocrine Microadenomatosis in Patients with a Von Hippel-Lindau Disease (Vhl) Périgny Martine, Pascal Hammel, Olivier Corcos, Stéphane Richard, Alain Sauvanet, Jacques Belghiti, Pierre Bedossa, Philippe B. Ruszniewski, Anne Couvelard VHL is an inherited cancer family syndrome caused by germline mutation in the VHL tumor suppressor gene predisposing to pancreatic endocrine tumors (PET). Whether these tumors derive from pre-existing endocrine microadenomatosis as in multiple endocrine neoplasia type 1 (MEN1) is yet unknown. However, inactivation of pVHL, responsible for accumulation of HIF (hypoxia inducible factor) and downstream genes such as VEGF (vascular endothelial cell growth factor), CA9 (carbonic anhydrase 9) and cyclin D1, could result in microscopic endocrine tumorigenesis. Our aim was thus to look for overexpression of these molecules, in order to identify precursor endocrine lesions in the pancreas of patients with VHL disease. Methods: Non-tumoral pancreas of 17 VHL patients, operated on for PET, was examined for microadenomatosis (≤5 mm) and compared with pancreatic specimen obtained from MEN1 patients (n=5) and controls without tumor disease (n=8). The immunohistochemical expression of chromogranin, insulin, glucagon, HIF-1alpha, VEGF, CA9 and cyclin D1 was assessed. Results: In addition to 35 macrotumors (6-50 mm,1-5 per patient), chromograninpositive endocrine microadenomas were found in 12 (70%) patients (1- ≥20 micronodules per case) located within acini or close to ducts or islets. Strong co-expression of HIF-1alpha, cyclin D1, CA9 and VEGF and lack of expression of insulin and glucagon allowed clear distinction with normal islets. CD34 identified a high microvessel density in these nodules. Expression of HIF-1alpha, cyclin D1 and CA9 was not found in islets of controls and in MEN1 microadenomas. In conclusion, pancreatic endocrine microadenomatosis is present in > 2/3 of VHL patients operated on for PET. These results demonstrate that the VHL/HIF pathway is involved very early in pancreatic endocrine tumorigenesis in this disease.
W1414 Detection of Chromosomal Aberrations in Intraductal Papillary Mucinous Neoplasms By Comparative Genomic Hybridization Stefan Fritz, Carlos Fernandez-del Castillo, Mari Mino-Kenudson, Stefano Crippa, Julie M. Miller, Sarah P. Thayer, Vikram Deshpande, Gregory Y. Lauwers, Andrew L. Warshaw, A. John Iafrate Background & Aims: Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) are characterized by progression from initially indolent intraductal growth to later aggressive malignant transformation. The biological behavior of IPMNs is different from and consequent survival after surgical resection better than that of pancreatic ductal adenocarcinoma. Although a number of shared genetic mutations have been identified, the molecular mechanisms underlying the clinical behavior of IPMNs are incompletely understood. Array-based comparative genetic hybridization (array CGH) allows identification and localization of genes that contribute to neoplastic development. Methods: A series of 17 IPMN specimens (4 females and 13 males) was prospectively identified and subdivided by histology criteria into those with low-grade dysplasia (n=6), moderate dysplasia (n=5), and malignant IPMN (highgrade dysplasia and invasive cancer) (n=6). DNA was isolated from fresh frozen tissue, and array CGH was performed using high-resolution oligonucleotide arrays. Results: With array CGH, none of the IPMNs with low-grade dysplasia displayed chromosomal aberrations. In contrast, IPMNs with moderate dysplasia showed an average of 3.6 gains (range 1-8) and 8.4 losses (range 3-16), and malignant IPMNs had an average of 5.3 gains (range 1-10) and 9.8 losses (range 5-14). In IPMNs with moderate dysplasia and in malignant IPMNs, loss of 6q occurred in 100% and 83.3% respectively, while a gain of chromosome 7 was found in 63.6%. Other commonly lost regions were located on chromosome 2, 5q, 8, 10q, 11q, 13q, 15q, 18q, and 22. Distinct high-level amplifications were seen on 8q23.1-telomer and 12p. Conclusions: These data provide evidence for a number of cytogenetically defined recurrent aberrations which are characteristic for IPMNs. While some are similar to ductal adenocarcinoma, some are distinct. The observations may provide a basis for understanding the unique biologic and clinical behavior of intraductal papillary mucinous neoplasms.
W1412 Expression of Sox-11 and Sox-4 Is Involved in Pathogenesis of Solid Pseudopapillary Tumor in Pancreas Jae Hee Cho, Sung Pil Hong, Jeong Youp Park, Tae Joo Jeon, Hee Man Kim, Seungmin Bang, Si Young Song, Jae Bock Chung, Seung Woo Park Background and aim: Solid-pseudopapillary tumor (SPT) of the pancreas has distinctive morphologic and biologic features, but its pathogenesis and clinical behavior are still unclear. Immunohistochemistry of specific markers for each cell lineage could not reach consistent conclusion and some hypotheses were suggested that SPT might be derived from acinar, endocrine, and genital-ridge/ovarian anlage-related cells. Previous our immunohistochemistry data showed overexpression of NOV and RIMS in SPT, which were related to neural crest development. Our cDNA microarray using Affymetrix HG U133 in 47 normal and 2 SPT tissues indicated that SOX-11 was increased 42 fold change compared to normal pancreas. SOX-11 was related to both neural crest development and neurite growth, and SOX-4 was expected to have similar biochemical activities to SOX-11 in neural tissue(c-DNA Microarray FC: 4). Therefore, we aimed to elucidate the pathogenesis of SPT by analysis of SOX-11 and SOX-4 expression in SPT. Materials and Methods: Thirty four SPT specimens obtained by surgical resection were collected. Three normal pancreas and three pancreatic adenocarcinoma were collected to use as a control. Immunohistochemical stain for SOX-11 and SOX4 was performed respectively using standard method and graded by two independent observers using stain intensity and immunoreactivity for the nuclear protein, strong grade in more than 80% of the cells and weak in 10% to 50% of the cells. Results: Among 34 cases of SPT (male to female ratio: 5/29, median age: 31.5 range 13-59). 13 (38.2%) cases were SPT suggesting malignant potential (5 peripancreatic invasion, 3 capsular invasion, 3 perineural invasion, 1 lymph node metastasis, 1 liver metastasis). One case with lymph node metastasis recurred at 8 months after surgical resection. The expression of SOX-11 was found at nucleus and SOX-4 at both cytoplasm and nucleus. In normal pancreas and pancreatic adenocarcinoma, there was no definite expression of SOX-11 and SOX-4. The positive expression was defined as above weak grade, SOX-11 and SOX-4 were verified in 28 (82.4%) and 32 (94.1%) of the 34 cases. As above moderate grade, SOX-11 in 22 (64.7%) and SOX-4 in 19 (55.9%). However there was no correlation between the characteristics of SPT including malignant potential and stain grade or intensity degree. Conclusion: We have demonstrated SOX 11 and SOX 4 overexpression in SPT. These data implied that neural crest development process is one of the tumorigenesis possibilities in SPT.
W1415 Natural History and Morphological Evolution of Pancreatic Serous Cystadenoma (sc) Vinciane Rebours, Marie-Pierre Vullierme, Alain Aubert, Anne-Laure Pelletier, Olivia Hentic, Frédérique Maire, Pascal Hammel, Philippe B. Ruszniewski, Philippe Levy Introduction SC is common pancreatic cystic neoplasm's. Risk of malignant transformation is very low and a surgical resection is not recommended. However, the natural history and the morphological evolution of SC are unknown on short and long term follow up. Aims To describe the clinical and morphological evolution of SC on long term follow up in a medical series. Patients and methods All patients with a SC diagnosed between 1995 and 2006 were included in this retrospective series. The SC diagnosis was realized by radiological procedures (CT scan or endoscopic ultrasonography (EUS) or MRI) or by fine needle aspiration. In the typical form, diagnostic criteria were the presence of a multicystic lesion with a multilocular form and a fine layer (<2 mm), composed by numerous little cysts (<2cm). At the beginning of the study and for the atypical form, an aspiration by fine needle was realized for pathological examination and biochemical analyses: ECA (<5 ng/mL), CA 72-4 (< 40U/ml) and pancreatic enzymes. A medical visit and a radiological procedure were realized every 3 years. Results 51 patients were included (females: 84%, median age at diagnosis: 55 years). Morphological procedures realized at diagnosis were respectively CT scan, EUS and MRI in 90%, 92% and 47%. Diagnosis was made by radiological procedures only (29%), associated with a fine needle aspiration (69%), or pathological examination (2%). Symptoms at diagnosis were: incidentally (86%), weight loss (6%), pancreatic pain (6%) and acute pancreatitis (2%). Location of SC was the pancreatic head (43%), the tail (51%) or the uncus (6%). Morphological features at diagnosis were: micro (79%) and macrocystic form (more than a cyst > 2 cm : 21%), unilocular (8%), central calcification (16%), vegetation (4%), main pancreatic duct compression (8%) or common bile duct compression (2%). The median follow up was 56 months (median number of radiological procedures: 2). Median SC diameter was at diagnosis and at last radiological procedure 30 and 35 mm, respectively (NS). No morphological modification was observed. No treatment was proposed for 49 patients. A surgical resection was realized in 2 patients and an evacuation by aspiration for one patient (common bile duct compression). Conclusion SC is usually discovered incidentally in the process of work up. After a 4 years follow up, no clinical event or morphological modification were diagnosed. These results justify the abstention of surgical resection if there is no diagnostic doubt. A long term follow up with a larger cohort is however necessary to confirm these data.
W1413 Proteomic Assessment of Markers for Malignancy in the Mucus of Intraductal Papillary Mucinous Neoplasms of the Pancreas (IPMN) Olivier Corcos, Anne Couvelard, Alain Sauvanet, Delphine Dargère, Frédérique Maire, Valérie Paradis, Pascal Hammel, Philippe Lévy, Philippe B. Ruszniewski, Pierre Bedossa Background and aim: IPMN gradually evolve from low grade dysplasia to invasive adenocarcinoma. Mucus secreted by tumoral epithelium is responsible for duct dilatation and might be obtained by fine-needle aspiration. Morphological, biochemical and cytological criteria do not allow accurate determination of IMPN malignancy. The aims of this study were 1 to look for differential protein expression in IPMN mucus according to histological grade,
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AGA Abstracts
AGA Abstracts
The expected number was 0.25 and SIR of pancreatic ductal adenocarcinomas was 15.8 (95% confidence interval (CI) 4.3-40.4; p=0.00014). Subgroup analyses showed that the incidence of pancreatic ductal adenocarcinomas was significantly increased in 70 years or older (SIR 16.7; 95% CI 3.4-48.7; p=0.0008) and in females (SIR 22.5; 95% CI 2.7-81.1; p=0.0037). Conclusions: Patients with Br-IPMNs have a markedly increased risk of pancreatic ductal adenocarcinomas compared with the general population. Follow-up with careful examination should be required to detect ductal adenocarcinomas apart from Br-IPMNs in the same pancreas.
PETs. Reproducibility is better for MIB-1 proliferation index and SST2 expression than for microvascular density. Sampling variability should be taken into consideration as a potential limitation to the assessment of prognostic and therapeutic markers in biopsy samples from metastatic PETs.
W1408 Senescence in Intraductal Papillary Mucinous Neoplasms of the Pancreas Yoshihiro Miyasaka, Eishi Nagai, Kenoki Ohuchida, Kohei Nakata, Akifumi Hayashi, Kazuhiro Mizumoto, Koji Yamaguchi, Masazumi Tsuneyoshi, Masao Tanaka Background/Aim: Senescence is a stable arrest of cell proliferation which was originally reported in cultured human fibroblasts through a finite number of passages. Recent studies reported that senescence was observed in neoplasms, especially in premalignant lesions, and played a role as a barrier against malignant progression. Previously, we reported that DNA damage checkpoint activation, which is considered to induce senescence in premalignant lesion, was observed in the early stage of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and diminished in the malignant IPMNs. In the current study, we analyzed several senescence markers, including senescence-associated beta-galactosidase (SA betagal) expression, formation of senescence-associated heterochromatin foci (SAHF) and p16 expression in IPMNs with different grades of dysplasia (adenoma, borderline, carcinoma in situ and invasive carcinoma) to verify senescence in IPMNs. Materials and Methods: Frozen sections from 33 IPMN patients (15 adenoma, 4 borderline, 10 carcinoma in situ, and 4 invasive carcinoma) were subjected to the analysis of SA beta-gal expression and immunofluorescence of HP1-gamma, which is a marker of SAHF. Formalin-fixed paraffin embedded sections from 117 IPMN patients (46 adenoma, 26 borderline, 21 carcinoma in situ, and 24 invasive carcinoma) were subjected to immunohistochemical staining of p16. Result: The positive rate of SA beta-gal expression is the highest in adenoma and gradually decreases according to the progression of dysplasia (80% of adenoma, 75% of borderline, 50% of carcinoma in situ, and 25% of invasive carcinoma). Most of the SA beta-gal expressing lesions also displayed SAHF formation. Expression of p16 showed similar tendency to the other two markers: 89% of adenoma, 80% of borderline, 67% of carcinoma in situ, and 46% of invasive carcinoma were positive for p16 staining. Conclusion: Senescence is induced in the early stage of IPMNs and gradually attenuated according to the progression of dysplasia, suggesting that senescence plays a significant role in preventing the tumor progression and its attenuation allows the malignant transformation of IPMNs.
W1406 Risk Factors for Pancreatic Endocrine Tumors: Multicentre Case-Control Study Gabriele Capurso, Massimo Falconi, Francesco Panzuto, Maria Rinzivillo, Rossella Bettini, Michela Di Fonzo, Letizia Boninsegna, Sara Cassetta, Vito D. Corleto, Paolo Pederzoli, Gianfranco Delle Fave Context: Pancreatic endocrine tumors (PETs) are rare neoplasms with an incidence of 0,1/ 100000. Apart from genetic disorders, risk factors for their occurrence have never been investigated. Smoking, drinking and obesity have been found to be risk factors for GI carcinoids and pancreatic ductal adenocarcinoma (PDAC). The possible role of family history has not been evaluated in GI endocrine tumors before. Aim: to determine risk factors for the occurrence of PETs. Methods: Multicentre C-C study. Patients with either new diagnosis of sporadic PET or in follow-up seen during a 12-month period were administered a questionnaire registering data on smoking, alcohol intake, BMI 1 year before PET diagnosis, and family history of cancer. Controls were patients with non-neoplastic, non-chronic disorders. Fisher test and wilcoxon test were used as appropriate. Univariate and multivariate analysis were performed by using a logistic regression model. Results: 146 patients (50% F) and 275 controls (52% F) enrolled. Mean age 52,5 for PETs and 53,8 for controls. 39,6% of PETs and 30,3% of controls were smokers (p=0.07). A pack x year (no.of daily packs x years of smoking)>20 more frequent amongst PETs (21% vs 15,4%; p=0.03). Drinking more frequent in PETs (35,3%) than controls (23,1%) (p=0.01). The median BMI was 24 (1740) in PETs and 25 (17-38) in controls (p=0.178), with obesity similarly distributed (9,7% vs 10,2%). 54,5% of PETS had at least one 1st degree family member with a neoplasm vs 36,4% of controls (p=0.0004). 15.9% of PETs had >2 1st degree family members with a neoplasm vs 5,1% of controls (p=0.0004). 33,1% of PETs and 10,5% controls had both 1st and 2nd degree cancer family history (p<0.000001). PDAC 1st or 2nd degree family history was found in 7,5% of PETs and 1.8% of controls (p=0.009). All 7 PETs with PDAC 1st degree family history were NF. No other site specific neoplasm family history significantly different. At a univariate analysis, drinking (OR 1,13 per increase in alcohol unit), 1st degree family history of any cancer (OR 2,06), 1st+2nd degree cancer family history (OR 4,1), PDAC 1st degree family history (OR 6,8) and PDAC 1st or 2nd degree family history (OR 4,3) were significant risk factors, with only 1st degree family history of any cancer (OR 1,7) and 1st or 2nd degree family history of PDAC (OR 3,2) significant by multivariate analysis. Conclusions: family history of cancer, particularly of PDAC, seem risk factors for PETs. This last finding is interesting as PETs occur also in families with familial PDAC. Smoking and drinking seem to show a trend toward an increased risk.
W1409 The Incidence of Other Malignancies in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas: Emphasis On Whole-Body Surveillance Ikuya Miki, Hiromu Kutsumi, Tetsuo Ajiki, Ippei Matsumoto, Shiei Yoshida, Yoshinori Morita, Takashi Toyonaga, Masaru Yoshida, Hideto Inokuchi, Shigeto Mizuno, Takeshi Azuma Background: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are believed to progress slowly showing a spectrum of neoplastic transformations, which are characterized by a favorable prognosis. Therefore, other malignancies may have a potential significance for prognosis in patients with IPMNs. Aims: In order to determine an appropriate surveillance strategy of extrapancreatic cancers, we examined the incidence and characteristics of preexisting, coexisting and subsequent malignancies in patients with IPMNs in Japan. Methods: Medical records were reviewed retrospectively in patients with IPMNs treated in Kobe University Hospital during 1990-2007. History of a prediagnostic, a concurrent, or a postdiagnostic development of an extrapancreatic neoplasm was investigated thoroughly. IPMNs were diagnosed by multiple radiographic modalities including abdominal ultrasonography, computed tomography, magnetic resonance cholangio-pancratography, and endoscopic retrograde pancreatography. Results: One hundred four patients were diagnosed as IPMNs (male: female=66:38, mean age; 64.5±8.2 years). Postdiagnostic follow-up period was 6.3±3.9 years (range, 0.2-12 years). Of these, 47 showed main duct type and 57 branched type. Eighty-two patients underwent surgery, and histological diagnosis was confirmed. Of 104 patients with IPMNs, 31 (29.7%) developed 36 extrapancreatic malignancies, which were found before (n = 18), at (n = 12) and after (n = 6) the diagnosis of IPMNs. Major associated malignancies were gastric cancer (n = 17), pulmonary cancer (n = 4), urological cancer (n= 4), breast cancer (n=4), colorectal cancer (n = 3), laryngeal cancer (n=1), cervical cancer (n=1), biliary tract cancer (n=1) and thyroid cancer (n=1). Extrapancreatic malignancies were sometimes detected by PET. Comparisons of the clinicopathological features in IPMNs with and without other malignancies revealed no significant differences in age, sex, location of the pancreas, type of IPMNs, or histological findings of IPMNs. Conclusion: IPMNs are associated with a high incidence of variable extrapancreatic neoplasms regardless of clinicopathological features, and a special notice is that one third patients with IPMNs would develop other malignancies. At the diagnosis of IPMNs, systemic surveillance, at least esophagogastroscopy, colonoscopy, mammography and chest CT, should be considered in order to detect second tumors. If possible, consultation with urology and gynecology is also needed. PET will be one of the most useful surveillance modalities in the future.
W1407 Regiv Expression Is Involved in ‘Intestinal Type' Carcinogenesis of Intraductal Papillary Mucinous Neoplasm of the Pancreas Kohei Nakata, Eishi Nagai, Kenoki Ohuchida, Yoshihiro Miyasaka, Akifumi Hayashi, Kazuhiro Mizumoto, Masazumi Tsuneyoshi, Masao Tanaka Background/Aims: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas show broad spectrum of dysplasia ranging from adenoma to carcinoma. Recently, IPMN is subclassified into 4 types including gastric, intestinal, oncocytic, and pancreatobiliary (PB)-types based on histological phenotypes. PB-type and intestinal-type IPMNs have been reported to associated with tubular invasion and mucinous invasion, respectively. Regenerating gene (REG) IV is secreted protein and dysregulation of RegIV expression is associated with an early step of the adenoma-carcinoma sequence. In the present study, we investigated the RegIV expression in a large cohort of patients with IPMNs, focusing on both the grade of atypia and histological subtypes. Materials and Methods: IPMNs were analyzed by imunohistochemical staining of RegIV. The lesions were classified as adenoma (IPMA), borderline (IPMB) and carcinoma (IPMC) on the basis of dysplasia, and also subdivided into four groups based on histological phenotype. Results: Of 127 IPMNs, 64 (54%) were subclassified as gastric-type, 38 (30%) as intestinal-type, eight (7%) as PB-type, three (2%) as oncocytictype, and eight (7%) as unclassified type. All of the invasive components in the gastric-, PB-, oncocytic- and unclassified neoplasms (6, 7, 1 and 3 IPMNs, respectively) displayed a tubular invasive pattern, whereas five of six (83%) intestinal-type IPMNs and two of five (40%) unclassified-type IPMNs with invasive components showed a mucinous noncystic pattern. Intestinal-, PB- and unclassified type IPMNs showed significantly high grade of atypia compared with gastric-type IPMNs (P<0.05). Of 126 IPMNs, 59 (46%) demonstrated positive staining of RegIV. The positive rate of RegIV of intestinal-, gastric-, PB- , oncocyticand unclassified IPMNs were 38/38 (100%), 18/68 (26%), 0/8 (0%), 0/ 3 (0%) and 3/8 (38%), respectively. Compared with IPMA (18/52, 35%), RegIV expression was observed more frequently in borderline IPMB (19/28, 68%) and IPMC (22/45, 48%). In analyses of IPMC cases, RegIV expression was observed more frequently in intestinal-type (18/18, 100%) than in PB- (0/8, 0%), oncocytic- (0/3. 0%), gastric- (1/8, 16%) and unclassified type (3/ 8, 38%). Five of seven (86%) mucinous invasive carcinomas showed positive Reg IV expression, while only one (6%) of 17 tubular invasive carcinomas did so. Conclusion: Reg IV expression was found more frequently in intestinal type IPMN including mucinous carcinoma than in the other types of IPMN including tubular invasive carcinoma, suggesting that RegIV might be involved in ‘intestinal type' carcinogenesis of IPMN of the pancreas.
AGA Abstracts
W1410 Risk of Pancreatic Ductal Adenocarcinomas in Long-Term Followed-Up Patients with Branch Duct Intraductal Papillary-Mucinous Neoplasms Satoshi Tanno, Tomoya Nishikawa, Kazuya Koizumi, Junpei Sasajima, Kazumasa Nakamura, Yusuke Mizukami, Toshikatsu Okumura, Yutaka Kohgo Background: Although branch duct type intraductal papillary-mucinous neoplasms (BrIPMNs) are reported to be slow-growing tumors with a favorable prognosis, the risk of pancreatic ductal adenocarcinomas apart from branch duct lesions in patients with Br-IPMNs is unknown. Objective: The aim of this study was to elucidate the incidence and risk of pancreatic ductal adenocarcinomas in long-term followed-up patients with Br-IPMNs. Methods: We studied a prospective and single center cohort of 89 consecutive patients (56 (62.9%) men, median age 68 years) with Br-IPMNs and a follow-up of at least two years (median follow-up 64 months; range 24-158) in order to exclude other cystic neoplasms or pseudocysts. We calculated the age and sex standardized incidence ratio (SIR) as the ratio as provided by Japanese Journal of Health and Welfare Statistics. Results: Four cases of pancreatic ductal adenocarcinomas (4.5% of patients) distant from Br-IPMN in the same pancreas were observed in 552 patients years of follow-up (7.2 per 1,000 patient years).
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using a differential proteomic technique; 2 - to identify proteins associated to malignant IPMN transformation, thus constituting specific biomarkers. Material and Methods: 43 mucus samples were obtained from surgically-resected IPMN in 43pts. IPMN were benign (lowand moderate-grade dysplasia) and malignant (high-grade dysplasia and invasive adenocarcinoma) in 21 and 22 pts, respectively. After protein extraction and quantitative assessment, mass spectrometry SELDI-TOF (Surface Enhanced Laser Desorption Ionisation-Time-OfFlight) was used to determine protein expression profiles in IPMN mucus. Protein peaks that significantly differed between benign and malignant IPMN (AUC > 0.88, p<10-4 with high intensity) were identified using Ciphergen express software and compared. Results : Among 952 protein peaks identified by SELDI-TOF, 31 were differentially expressed in benign and malignant IPMN (p <0.001). Among them, 5 proteins of interest were selected due to high diagnostic accuracy and ability to distinguish between the 2 groups of tumors. Proteic weights (m/z) were 5217, 6326, 6719, 10453 and 10849 Da, respectively. There was no correlation between protein expression and IPMN type (branch-duct, main-duct, combined). Conclusion : Multistep carcinogenic process in IPMN is associated with differential protein expression that can be identified in the mucus secreted by tumoral epithelium. Mass spectrometry allows to characterize proteins that could be associated with malignant transformation. Proteins identification is on progress.
W1411 In Situ Detection of Vhl/HIF Pathway Proteins Identifies a Pancreatic Endocrine Microadenomatosis in Patients with a Von Hippel-Lindau Disease (Vhl) Périgny Martine, Pascal Hammel, Olivier Corcos, Stéphane Richard, Alain Sauvanet, Jacques Belghiti, Pierre Bedossa, Philippe B. Ruszniewski, Anne Couvelard VHL is an inherited cancer family syndrome caused by germline mutation in the VHL tumor suppressor gene predisposing to pancreatic endocrine tumors (PET). Whether these tumors derive from pre-existing endocrine microadenomatosis as in multiple endocrine neoplasia type 1 (MEN1) is yet unknown. However, inactivation of pVHL, responsible for accumulation of HIF (hypoxia inducible factor) and downstream genes such as VEGF (vascular endothelial cell growth factor), CA9 (carbonic anhydrase 9) and cyclin D1, could result in microscopic endocrine tumorigenesis. Our aim was thus to look for overexpression of these molecules, in order to identify precursor endocrine lesions in the pancreas of patients with VHL disease. Methods: Non-tumoral pancreas of 17 VHL patients, operated on for PET, was examined for microadenomatosis (≤5 mm) and compared with pancreatic specimen obtained from MEN1 patients (n=5) and controls without tumor disease (n=8). The immunohistochemical expression of chromogranin, insulin, glucagon, HIF-1alpha, VEGF, CA9 and cyclin D1 was assessed. Results: In addition to 35 macrotumors (6-50 mm,1-5 per patient), chromograninpositive endocrine microadenomas were found in 12 (70%) patients (1- ≥20 micronodules per case) located within acini or close to ducts or islets. Strong co-expression of HIF-1alpha, cyclin D1, CA9 and VEGF and lack of expression of insulin and glucagon allowed clear distinction with normal islets. CD34 identified a high microvessel density in these nodules. Expression of HIF-1alpha, cyclin D1 and CA9 was not found in islets of controls and in MEN1 microadenomas. In conclusion, pancreatic endocrine microadenomatosis is present in > 2/3 of VHL patients operated on for PET. These results demonstrate that the VHL/HIF pathway is involved very early in pancreatic endocrine tumorigenesis in this disease.
W1414 Detection of Chromosomal Aberrations in Intraductal Papillary Mucinous Neoplasms By Comparative Genomic Hybridization Stefan Fritz, Carlos Fernandez-del Castillo, Mari Mino-Kenudson, Stefano Crippa, Julie M. Miller, Sarah P. Thayer, Vikram Deshpande, Gregory Y. Lauwers, Andrew L. Warshaw, A. John Iafrate Background & Aims: Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) are characterized by progression from initially indolent intraductal growth to later aggressive malignant transformation. The biological behavior of IPMNs is different from and consequent survival after surgical resection better than that of pancreatic ductal adenocarcinoma. Although a number of shared genetic mutations have been identified, the molecular mechanisms underlying the clinical behavior of IPMNs are incompletely understood. Array-based comparative genetic hybridization (array CGH) allows identification and localization of genes that contribute to neoplastic development. Methods: A series of 17 IPMN specimens (4 females and 13 males) was prospectively identified and subdivided by histology criteria into those with low-grade dysplasia (n=6), moderate dysplasia (n=5), and malignant IPMN (highgrade dysplasia and invasive cancer) (n=6). DNA was isolated from fresh frozen tissue, and array CGH was performed using high-resolution oligonucleotide arrays. Results: With array CGH, none of the IPMNs with low-grade dysplasia displayed chromosomal aberrations. In contrast, IPMNs with moderate dysplasia showed an average of 3.6 gains (range 1-8) and 8.4 losses (range 3-16), and malignant IPMNs had an average of 5.3 gains (range 1-10) and 9.8 losses (range 5-14). In IPMNs with moderate dysplasia and in malignant IPMNs, loss of 6q occurred in 100% and 83.3% respectively, while a gain of chromosome 7 was found in 63.6%. Other commonly lost regions were located on chromosome 2, 5q, 8, 10q, 11q, 13q, 15q, 18q, and 22. Distinct high-level amplifications were seen on 8q23.1-telomer and 12p. Conclusions: These data provide evidence for a number of cytogenetically defined recurrent aberrations which are characteristic for IPMNs. While some are similar to ductal adenocarcinoma, some are distinct. The observations may provide a basis for understanding the unique biologic and clinical behavior of intraductal papillary mucinous neoplasms.
W1412 Expression of Sox-11 and Sox-4 Is Involved in Pathogenesis of Solid Pseudopapillary Tumor in Pancreas Jae Hee Cho, Sung Pil Hong, Jeong Youp Park, Tae Joo Jeon, Hee Man Kim, Seungmin Bang, Si Young Song, Jae Bock Chung, Seung Woo Park Background and aim: Solid-pseudopapillary tumor (SPT) of the pancreas has distinctive morphologic and biologic features, but its pathogenesis and clinical behavior are still unclear. Immunohistochemistry of specific markers for each cell lineage could not reach consistent conclusion and some hypotheses were suggested that SPT might be derived from acinar, endocrine, and genital-ridge/ovarian anlage-related cells. Previous our immunohistochemistry data showed overexpression of NOV and RIMS in SPT, which were related to neural crest development. Our cDNA microarray using Affymetrix HG U133 in 47 normal and 2 SPT tissues indicated that SOX-11 was increased 42 fold change compared to normal pancreas. SOX-11 was related to both neural crest development and neurite growth, and SOX-4 was expected to have similar biochemical activities to SOX-11 in neural tissue(c-DNA Microarray FC: 4). Therefore, we aimed to elucidate the pathogenesis of SPT by analysis of SOX-11 and SOX-4 expression in SPT. Materials and Methods: Thirty four SPT specimens obtained by surgical resection were collected. Three normal pancreas and three pancreatic adenocarcinoma were collected to use as a control. Immunohistochemical stain for SOX-11 and SOX4 was performed respectively using standard method and graded by two independent observers using stain intensity and immunoreactivity for the nuclear protein, strong grade in more than 80% of the cells and weak in 10% to 50% of the cells. Results: Among 34 cases of SPT (male to female ratio: 5/29, median age: 31.5 range 13-59). 13 (38.2%) cases were SPT suggesting malignant potential (5 peripancreatic invasion, 3 capsular invasion, 3 perineural invasion, 1 lymph node metastasis, 1 liver metastasis). One case with lymph node metastasis recurred at 8 months after surgical resection. The expression of SOX-11 was found at nucleus and SOX-4 at both cytoplasm and nucleus. In normal pancreas and pancreatic adenocarcinoma, there was no definite expression of SOX-11 and SOX-4. The positive expression was defined as above weak grade, SOX-11 and SOX-4 were verified in 28 (82.4%) and 32 (94.1%) of the 34 cases. As above moderate grade, SOX-11 in 22 (64.7%) and SOX-4 in 19 (55.9%). However there was no correlation between the characteristics of SPT including malignant potential and stain grade or intensity degree. Conclusion: We have demonstrated SOX 11 and SOX 4 overexpression in SPT. These data implied that neural crest development process is one of the tumorigenesis possibilities in SPT.
W1415 Natural History and Morphological Evolution of Pancreatic Serous Cystadenoma (sc) Vinciane Rebours, Marie-Pierre Vullierme, Alain Aubert, Anne-Laure Pelletier, Olivia Hentic, Frédérique Maire, Pascal Hammel, Philippe B. Ruszniewski, Philippe Levy Introduction SC is common pancreatic cystic neoplasm's. Risk of malignant transformation is very low and a surgical resection is not recommended. However, the natural history and the morphological evolution of SC are unknown on short and long term follow up. Aims To describe the clinical and morphological evolution of SC on long term follow up in a medical series. Patients and methods All patients with a SC diagnosed between 1995 and 2006 were included in this retrospective series. The SC diagnosis was realized by radiological procedures (CT scan or endoscopic ultrasonography (EUS) or MRI) or by fine needle aspiration. In the typical form, diagnostic criteria were the presence of a multicystic lesion with a multilocular form and a fine layer (<2 mm), composed by numerous little cysts (<2cm). At the beginning of the study and for the atypical form, an aspiration by fine needle was realized for pathological examination and biochemical analyses: ECA (<5 ng/mL), CA 72-4 (< 40U/ml) and pancreatic enzymes. A medical visit and a radiological procedure were realized every 3 years. Results 51 patients were included (females: 84%, median age at diagnosis: 55 years). Morphological procedures realized at diagnosis were respectively CT scan, EUS and MRI in 90%, 92% and 47%. Diagnosis was made by radiological procedures only (29%), associated with a fine needle aspiration (69%), or pathological examination (2%). Symptoms at diagnosis were: incidentally (86%), weight loss (6%), pancreatic pain (6%) and acute pancreatitis (2%). Location of SC was the pancreatic head (43%), the tail (51%) or the uncus (6%). Morphological features at diagnosis were: micro (79%) and macrocystic form (more than a cyst > 2 cm : 21%), unilocular (8%), central calcification (16%), vegetation (4%), main pancreatic duct compression (8%) or common bile duct compression (2%). The median follow up was 56 months (median number of radiological procedures: 2). Median SC diameter was at diagnosis and at last radiological procedure 30 and 35 mm, respectively (NS). No morphological modification was observed. No treatment was proposed for 49 patients. A surgical resection was realized in 2 patients and an evacuation by aspiration for one patient (common bile duct compression). Conclusion SC is usually discovered incidentally in the process of work up. After a 4 years follow up, no clinical event or morphological modification were diagnosed. These results justify the abstention of surgical resection if there is no diagnostic doubt. A long term follow up with a larger cohort is however necessary to confirm these data.
W1413 Proteomic Assessment of Markers for Malignancy in the Mucus of Intraductal Papillary Mucinous Neoplasms of the Pancreas (IPMN) Olivier Corcos, Anne Couvelard, Alain Sauvanet, Delphine Dargère, Frédérique Maire, Valérie Paradis, Pascal Hammel, Philippe Lévy, Philippe B. Ruszniewski, Pierre Bedossa Background and aim: IPMN gradually evolve from low grade dysplasia to invasive adenocarcinoma. Mucus secreted by tumoral epithelium is responsible for duct dilatation and might be obtained by fine-needle aspiration. Morphological, biochemical and cytological criteria do not allow accurate determination of IMPN malignancy. The aims of this study were 1 to look for differential protein expression in IPMN mucus according to histological grade,
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AGA Abstracts
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The expected number was 0.25 and SIR of pancreatic ductal adenocarcinomas was 15.8 (95% confidence interval (CI) 4.3-40.4; p=0.00014). Subgroup analyses showed that the incidence of pancreatic ductal adenocarcinomas was significantly increased in 70 years or older (SIR 16.7; 95% CI 3.4-48.7; p=0.0008) and in females (SIR 22.5; 95% CI 2.7-81.1; p=0.0037). Conclusions: Patients with Br-IPMNs have a markedly increased risk of pancreatic ductal adenocarcinomas compared with the general population. Follow-up with careful examination should be required to detect ductal adenocarcinomas apart from Br-IPMNs in the same pancreas.