Development Of Intraductal Papillary Mucinous Neoplasm Research Articles

Metabolic Syndrome Accelerates the Age-Related Increase of Intraductal Papillary Mucinous Neoplasm of the Pancreas.

Aging is associated with a high prevalence of pancreatic cysts and intraductal papillary mucinous neoplasms (IPMNs). Metabolic syndrome (MS) may increase the risk of neoplasms, including those that develop in the pancreas. However, the influence of factors associated with MS on the development of IPMN remains unclear. A total of 9363 patients who underwent abdominal ultrasound examinations between April 2012 and May 2013 were included in this study. Multivariate logistic regression analysis was performed to identify factors associated with the presence of IPMN by age. Pancreatic cysts were detected in 198 of 9363 patients, of whom 129 were found to have IPMNs. The presence of IPMN significantly correlated with age (10-year increments; odds ratio, 2.73; 95% CI, 2.28-3.29; P < 0.001). High body mass index, history of smoking, hyperlipidemia, hypertension, and MS were associated with a higher prevalence of IPMN with advancing age. In multivariate analysis, the presence of IPMN was more frequent in elderly patients with MS (odds ratio, 3.14; 95% CI, 3.14-6.72; P = 0.003). The present study suggests that the incidence of IPMN increases with age and is accelerated in the presence of MS.

Mechanisms of development and progression of pancreatic neoplasms.

Pancreatic ductal adenocarcinoma (PDAC) develops via dysplastic changes in the epithelia graded as low- and high-grade with accumulation of molecular alterations. Constitutive activation of mitogen-activated protein kinase (MAPK) contributed by attenuation of DUSP6 plays a key role in sustaining PDAC. Active MAPK induces various molecules that function as effectors to sustain PDAC. AURKA and SON are downstream effectors that contribute substantially to the proliferation and survival of PDAC cells and are potentially useful as therapeutic targets. Active MAPK also promote microRNAs that modulate the proliferation of PDAC cells and are useful as diagnostic markers. Familial pancreatic cancer kindreds in Japan show various germline mutations supposed to increase a pancreatic cancer risk. Intraductal papillary mucinous neoplasms (IPMNs) consist of dilated ducts lined by papillary neoplastic epithelia of various shapes and varying grades of atypia. Various papillae of IPMNs are classified into four subtypes that are associated with clinicopathological features, including patient prognosis. GNAS is a specific driver gene for the development of IPMN through gain-of-function mutations. Tracing of molecular alterations has elucidated the mechanism of progression of IPMN from dysplasia to carcinoma, as well as one type of papillae. Intraductal tubulopapillary neoplasms belong to a distinct class of pancreatic neoplasms.

Value of 3-T MR imaging in intraductal papillary mucinous neoplasm with a concomitant invasive carcinoma.

To examine the value of 3-T MRI for evaluating the difference between the pancreatic parenchyma of intraductal papillary mucinous neoplasm with a concomitant invasive carcinoma (IPMN-IC) and the pancreatic parenchyma of patients without an IPMN-IC. A total of 132 patients underwent abdominal 3-T MRI. Of the normal pancreatic parenchymal measurements, the pancreas-to-muscle signal intensity ratio in in-phase imaging (SIR-I), SIR in opposed-phase imaging (SIR-O), SIR in T2-weighted imaging (SIR-T2), ADC (×10-3 mm2/s) in DWI, and proton density fat fraction (PDFF [%]) in multi-echo 3D DIXON were calculated. The patients were divided into three groups (normal pancreas group: n = 60, intraductal papillary mucinous neoplasm (IPMN) group: n = 60, IPMN-IC group: n = 12). No significant differences were observed among the three groups in age, sex, body mass index, prevalence of diabetes mellitus, and hemoglobin A1c (p = 0.141 to p = 0.657). In comparisons among the three groups, the PDFF showed a significant difference (p < 0.001), and there were no significant differences among the three groups in SIR-I, SIR-O, SIR-T2, and ADC (p = 0.153 to p = 0.684). The PDFF of the pancreas was significantly higher in the IPMN-IC group than in the normal pancreas group or the IPMN group (p < 0.001 and p < 0.001, respectively), with no significant difference between the normal pancreas group and the IPMN group (p = 0.916). These observations suggest that the PDFF of the pancreas is associated with the presence of IPMN-IC. • The cause and risk factors of IPMN with a concomitant invasive carcinoma have not yet been clarified. • The PDFF of the pancreas was significantly higher in the IPMN-IC group than in the normal pancreas group or the IPMN group. • Pancreatic PDFF may be a potential biomarker for the development of IPMN with a concomitant invasive carcinoma.

Abstract 1102: Model optimization and chemoprevention of IPMN driven PDAC in KPSD4 mouse model

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with one of the lowest five-year survival rates. Patients with intraductal papillary mucinous neoplasms (IPMN) or mucinous cystic neoplasms (MCNs) are at high risk for the development of PDAC and thus are target populations for intervention with chemopreventive agents. The lack of optimized animal models of IPMNs has limited the development of chemopreventive agents and vaccines. We have thus characterized the suitability of the Pdx1Cre.LSL-KrasG12D.SMAD4flox/flox (KPSD4) model for IPMN formation and their progression to PDAC. In addition, as a proof-of-principle we assessed the chemopreventive efficacy of gefitinib in the KPSD4 model. The development of IPMNs and PDAC were monitored up to 44 weeks of age by serial sacrifice at 6, 12, 18, 24, 36, and 44 weeks of age in male and female KPSD4 mice (n=6/time point), at which time the pancreata were analyzed for lesion development. The KPSD4 mouse model developed both IPMNs and pancreatic intraepithelial neoplasia (PanINs) spontaneously. IPMNs were histologically classified as i) independent (single IPMN duct); ii) IPMN cluster/adenoma (multiple IPMN ducts as cluster or adenoma); iii) IPMN borderline (dysplasia with or without CIS); and iv) IPMN invasive carcinoma. At 6 weeks of age, the pancreata were normal in appearance (&amp;gt;94% in male; &amp;gt;97% female) with low frequency (Mean ± SEM) of PanINs (Male, 6.5±2.65; Female, 3.44±2.12) and IPMNs (Male, 5.5±2.21; Female, 2.56±0.96). At 12 weeks of age, there was a significant increase of IPMN number and their progression to borderline type that advanced to carcinoma by age 24 weeks. At 36 weeks of age, &amp;gt;80% of the KPSD4 mice developed carcinomas that rapidly spread to the entire pancreas by 44 weeks of age. Overall, IPMN progression to PDAC required somewhat less time than did the progression of PanINs to PDAC in the KPSD4 mouse model. A major limitation of the KPSD4 model was the mortality due to secondary phenotypes. In KPSD4 mice, ~40% mortality was observed between 6 and 18 weeks of age due to intestinal tumors leading to obstruction. For the chemopreventive efficacy bioassay, 6 week old male and female KPSD4 mice (34/group) were fed diets containing 0 or 100 ppm of gefitinib for 18 weeks. Mice were euthanized at 24 weeks of age and pancreata were assessed for IPMNs, PanINs, and PDAC. Control-diet-fed male and female mice showed IPMN driven PDAC incidences of 83% and 100%, respectively, whereas male and female KPSD4 mice exposed to 100 ppm gefitinib showed PDAC incidences of 50% and 27% (p&amp;lt;0.0006), respectively. A significant reduction of IPMN individual ducts, adenoma, and IPMN borderline was observed in KPSD4 mice fed gefitinib, thus demonstrating a strong suppression of IPMN individual duct progression to more advanced lesions upon treatment with gefitinib. [Supported by NCI HHSN261201500038I]. Citation Format: Gaurav Kumar, Venkateshwar Madka, Anil Singh, Nandini Kumar, Nicole Stratton, Stanley Lightfoot, Altaf Mohammed, Mark S. Miller, Chinthalapally V. Rao. Model optimization and chemoprevention of IPMN driven PDAC in KPSD4 mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1102.

Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas.

The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

Risk Factors for Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas: A Multicentre Case–Control Study

To investigate environmental, personal, and hereditary risk factors associated with the occurrence of intraductal papillary mucinous neoplasms of the pancreas (IPMNs). Multicentre case-control study. Risk factors were identified from a questionnaire collecting data on family and medical history, and environmental factors. Cases were prevalent IPMNs seen at the participating units within an 18-month timeframe. Matched controls were enrolled alongside patients seen at outpatient clinics. Three-hundred and ninety patients with IPMN and 390 matched controls (166 males, mean age 65 in each group) were enrolled. Of the IPMNs, 310 had branch-duct involvement and 80 main-duct involvement. The only cancer with a 1st degree family history significantly higher in IPMN was pancreatic ductal adenocarcinoma (PDAC) (5.4% vs. 1.5%). Previous history of diabetes (13.6% vs. 7.5%), chronic pancreatitis (CP) (3.1% vs. 0.3%), peptic ulcer (7.2% vs. 4.3%), and insulin use (4.9% vs. 1.1%) were all more frequent with IPMNs. Logistic regression multivariate analysis revealed that history of diabetes (odds ratio (OR): 1.79, confidence interval (CI) 95%: 1.08-2.98), CP (OR: 10.10, CI 95%: 1.30-78.32), and family histories of PDAC (OR: 2.94, CI 95%: 1.17-7.39) were all independent risk factors. However, when analysis was restricted to diabetics who had taken insulin, risk of IPMN became stronger (OR: 6.03, CI 95%: 1.74-20.84). The association with all these risk factors seemed stronger for the subgroup with main duct involvement. A previous history of diabetes, especially with insulin use, CP, and family history of PDAC are all relevant risk factors for the development of IPMN. These results suggest an overlap between certain risk factors for PDAC and IPMN.

MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasms (IPMN) represent a spectrum of tumors that range from low-grade (LG) dysplastic tumors to invasive cancer. Identification of IPMN at high risk for malignant transformation is important for the prevention and early treatment of pancreatic cancer. The roles of microRNA expression in the development of IPMN have not been extensively evaluated. Expression patterns of 846 human microRNAs (miRNAs) was analyzed using microRNA microarray in 55 tissues, including LG IPMN (n = 10), moderate-grade (MG) IPMN (n = 5), high-grade (HG) IPMN (n = 5), invasive cancer with IPMN (IPMC; n = 10), pancreatic ductal adenocarcinoma without IPMN (PDA; n = 5), LG IPMN extracted from specimens that contain IPMC(LG_Ca; n = 10), and normal pancreatic tissues (n = 10). Fourteen miRNAs were differentially expressed in all IPMN tissues compared with normal pancreatic tissue. Expression level of 3 miRNAs was proportional to dysplasia level. Hierarchical clustering demonstrated grouping of 2 IPMN subgroups: LG and MG IPMN verses HG IPMN and IPMC. Expression of 15 miRNAs was significantly different between these groups. LG_Ca tissues clustered with the HG IPMC group, and 12 miRNAs were differentially expressed in LG_Ca, HG lesions, and IPMC compared with LG lesions. The expression patterns of selected miRNAs were validated using quantitative reverse-transcription real-time polymerase chain reaction. Hierarchical clustering demonstrated microRNA expression profile in IPMC was significantly different from PDA, suggesting that different pathways are involved in these cancer types. This study demonstrates that miRNAs are involved in the development and progression of IPMN. We identified potential targets for diagnosis, prognostication, and treatment of IPMN.

Angiogenesis index CD105 (endoglin)/CD31 (PECAM-1) as a predictive factor for invasion and proliferation in intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is an increasingly diagnosed entity since its definition by the World Health Organization in 1996. It has a broad clinical spectrum ranging from benign to malignant tumors. Optimum treatment is controversial and a better understanding of the development of IPMN of the pancreas and identification of potential prognostic factors will help to address this. Angiogenesis plays an elementary role in the development of malignant tumors and may well also be important in the development of IPMN of the pancreas. Therefore we investigated endothelial cell marker CD31 (PECAM-1) and angiogenesis associated marker CD105 (endoglin) by immunohistochemistry. Thirty-two cases of surgically resected IPMN were chosen retrospectively and clinical data were obtained. Specimens were stained for proliferation marker (Ki-67), CD31 and CD105 by immunohistochemistry. A CD105/CD31 Angiogenesis ratio (AR) was established to determine the proliferating fraction of endothelial cells. The AR is significantly elevated in invasive IPMN of the pancreas (Mann-Whitney-U Test, p<0.05) and is associated with the Ki-67-labelling-index, demonstrating synergy between tumor-growth and neovascularisation. Invasive IPMN of the pancreas is associated with significantly lower recurrence-free and overall survival. Neovascularisation plays an important role in the tumorigenesis of invasive IPMN of the pancreas, and therefore angiogenesis-associated molecules like CD105 and CD31 might be useful tools as prognostic markers. Furthermore, the results indicate a potential role for adjuvant anti-angiogenic therapies in selected patients with recurring and/or invasive IPMN of the pancreas.

Expression of MSX2 predicts malignancy of branch duct intraductal papillary mucinous neoplasm of the pancreas

To distinguish malignant from benign branch duct (BD)-intraductal papillary mucinous neoplasm (IPMN) still remains difficult. Recently, we revealed that MSX2 was frequently expressed in pancreatic cancer and its expression was correlated with aggressive behavior of the cancer. The aim of this study was to assess the involvement of MSX2 in IPMN development and whether its expression would differentiate malignant from benign IPMN. Seventeen microdissected lesions and 45 IPMN tissues were used for quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The role of MSX2 in the pancreatic duct cell was assessed by the induced expression of MSX2 in a normal human pancreatic duct epithelial cell line (HPDE). Malignant IPMN expressed significantly higher levels of MSX2 mRNA than benign IPMN lesions. MSX2 protein expression was frequently found in borderline and malignant lesions (20/29, 68.9%), while its expression was seen in only one of 16 benign IPMN tissues. Univariate analysis showed that nodules of 6 mm or more and MSX2 expression were significantly correlated with the malignancy of BD-IPMN (P = 0.022 and 0.0026, respectively), and multivariate analysis revealed that only MSX2 expression was identified as an independent factor to predict malignant BD-IPMN. HPDE cells expressing MSX2 showed increased cellular proliferation compared to control cells. Based on our results, MSX2 plays a pivotal role in the development of IPMN through growth stimulation of tumor cells, and its expression was identified as an independent predictive factor for malignancy of BD-IPMN.

Pancreatic lithiasis and intraductal papillary‐mucinous neoplasm with special reference to the pathogenesis of lithiasis

In pancreatic lithiasis in elderly autopsy cases, the stones are small and the pancreatic duct is changed very slightly when viewed by simple X-ray film, pancreatic ductography and gross appearance. Histologically, a slight fibrous increase is seen very locally, but findings consistent with chronic pancreatitis are not found throughout the whole pancreas. However, marked, diffuse and irregular dilatation of the pancreatic duct is frequently found in operative cases with chronic pancreatitis and pancreatic stones. These findings show that the changes seen with aging and with chronic pancreatitis can be distinguished based on the findings of pancreatic ductography. Mucin production in epithelia in intraductal papillary-mucinous neoplasm (IPMN) may not be strongly associated with the pathogenesis of pancreatic lithiasis. Pancreatic lithiasis may be related to squamous cell metaplasia. IPMN and dilatation of the pancreatic duct are closely associated with mucin production. An increase in intraductal pressure of the pancreatic duct may be somewhat related to the mechanism of stone formation. The incidental co-existence of pancreatic epithelia with pancreatic lithiasis in patients with chronic pancreatitis and the development of IPMN may also be possible. IPMN and pancreatic lithiasis may be related through the mechanism(s) of their pathogenesis, their synergism and the pathogenesis of stone formation. The relation between mucinous metaplasia and stone formation is slight and, therefore, there may be only a weak correlation between IPMN and pancreatic stones. This may explain why there are few reports of the co-existence of IPMN and pancreatic stones (Kimura in Kan Tan Sui 58:485-492, 2009).

BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas

The Raf/MEK/ERK (MAPK) signal transduction is an important mediator of a number of cellular fates including growth, proliferation, and survival. The BRAF gene is activated by oncogenic RAS, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible role of BRAF in the development of IPMN (Intraductal Papillary Mucinous Neoplasm) and IPMC (Intraductal Papillary Mucinous Carcinoma) of the pancreas. Mutations of BRAF and KRAS were evaluated in 36 IPMN/IPMC samples and two mucinous cystadenomas by direct genomic sequencing. Exons 1 for KRAS, and 5, 11, and 15 for BRAF were examined. Totally we identified 17 (47%) KRAS mutations in exon 1, codon 12 and one missense mutation (2.7%) within exon 15 of BRAF. The mutations appear to be somatic since the same alterations were not detected in the corresponding normal tissues. Our data provide evidence that oncogenic properties of BRAF contribute to the tumorigenesis of IPMN/IPMC, but at a lower frequency than KRAS.

Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice

Intraductal papillary mucinous neoplasms (IPMNs) are common cystic tumours of the pancreas. Sonic hedgehog (SHH) is involved in gastric epithelial differentiation and pancreatic carcinogenesis. However, a comprehensive analysis of SHH expression in IPMN has not yet been performed. In the present study, one-step quantitative real-time reverse transcription-polymerase chain reaction with gene-specific priming was used to examine mRNA levels in various types of clinical samples. SHH expression in IPMN was measured and the possible association of gastric epithelial differentiation with development of IPMN was evaluated. In bulk tissue analyses (IPMNs, 11 pancreatic cancer, and 20 normal pancreatic tissues), IPMN expressed significantly higher levels of SHH than did normal pancreas (IPMN versus normal pancreas, p = 0.0025; pancreatic cancer versus normal pancreas, p = 0.0132), but SHH expression did not differ between IPMN and pancreatic cancer (p = 0.3409). In microdissection analyses (infiltrating ductal carcinoma cells from 20 sections, IPMN cells from 20 sections, pancreatitis-affected epithelial cells from 11 sections, and normal epithelial cells from 12 sections), IPMN cells expressed significantly higher levels of SHH than did cancer cells, normal cells, or pancreatitis-affected ductal cells (all comparisons, p < 0.008). Pancreatic juice analyses (20 samples from pancreatic cancers, 31 samples from IPMNs, and 27 samples from chronic pancreatitis) revealed that SHH expression differed significantly between IPMN juice and pancreatitis juice (p < 0.0001), and between cancer juice and pancreatitis juice (p = 0.0125). Receiver operating characteristic curve analyses revealed that SHH measurement in pancreatic juice was useful for discriminating IPMN from chronic pancreatitis (area under the curve = 0.915; 95% confidence interval: 0.796-0.976). The data suggest that overexpression of SHH is an early event in the development of IPMN and that SHH measurement in pancreatic juice may provide some advantages for the treatment or follow-up of a subset of patients with IPMN or chronic pancreatitis.

A Multicentric Development Of Intraductal Papillary Mucinous Neoplasm Treated By Repeated Pancreatectomy

There are few reports of multicentric recurrence after resection of lesions of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We report a case of repeated pancreatectomy for recurrent IPMN showing multicentric development in the pancreatic remnant after resection of the initial lesion. In February 1999 a 70-year-old man underwent distal pancreatectomy for a cystic neoplasm in the pancreatic tail. Histological examination revealed invasive intraductal papillary mucinous adenocarcinoma (IPMC) with lymph node metastasis. Forty-seven months later, a cystic mass with an intracystic nodule was detected during surveillance by computed tomography. The patient underwent completion pancreatectomy. Histological examination demonstrated IPMC with neural invasion. In immunohistochemical staining, the initial specimen was positive for proteinase-activated receptor 2, but the second specimen was not. The present case helps elucidate the multicentric development of IPMN of the pancreas. We recommend careful surveillance for the recurrence of IPMN in the pancreatic remnant after resection.

Intraductal papillary mucinous neoplasms of the pancreas: A surgical perspective

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas represent a relatively "new", but increasingly recognized entity. The emergence of this entity is due primarily to the widespread use of modern imaging methods, but also to a heightened awareness of physicians regarding this cystic neoplasm of the pancreas. No signs or symptoms are pathognomonic of IPMNs, but frequently, patients have a pancreatitis-like abdominal pain. Fully one-third of patients with IPMN are asymptomatic at the time of diagnosis. Cross-sectional imaging (ultrasonography, computed tomography, magnetic resonance cholangiopancreatography), endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography are the diagnostic and staging methods of choice in the evaluation of patients with IPMNs. IPMNs show a wide spectrum of histologic changes, ranging from adenoma to invasive neoplasm, even within the same neoplasm, suggesting a "field defect" predisposing major segments or even the entire ductal epithelium to the development of IPMN. Fine-needle aspiration/cytology and/or analysis of the cystic fluid may be useful diagnostic tools; however, these examinations are associated with high false-negative rates. Complete surgical resection is the therapeutic method of choice. The extent and type of pancreatectomy remain somewhat controversial but should be based on morphologic changes of the pancreas. Even the role of adjuvant therapy remains unclear; however, being "duct-derived" neoplasms of potential malignant character, some form of adjuvant chemo- or ratio-therapy seems indicated in the presence of invasive disease, despite a "curative" resection. In the absence of invasive disease, prognosis after R0 resection is highly favorable with recurrences of 5-10%. However, invasive IPMNs behave quite similar to ductal adenocarcinoma of the pancreas when analyzed stage-by-stage, with a slightly better prognosis; however, even after an R0 resection, recurrence is common.