Current considerations on intraductal papillary neoplasms of the bile duct and pancreatic duct

Pancreatobiliary intraductal papillary neoplasms(IPNs)represent precursors of pancreatic cancer or bile duct cholangiocarcinoma that can be detected and treated.Despite advances in diagnostic methods,identifying these premalignant lesions is still challenging for treatment providers.Modern imaging,biomarkers and molecular tests for genomic alterations can be used for diagnosis and follow-up.Surgical intervention in combination with new chemotherapeutic agents is considered the optimal treatment for malignant cases.The balance between the risk of malignancy and any risk of resection guides management policy;therefore,treatment should be individualized based on a meticulous preoperative assessment of high-risk stigmata.IPN of the bile duct is more aggressive;thus,early diagnosis and surgery are crucial.The conservative management of low-risk pancreatic branch-duct lesions is safe and effective.

Comparison of endoscopic ultrasound, computed tomography and magnetic resonance imaging in assessment of detailed structures of pancreatic cystic neoplasms

AIM To evaluate the advantages of endoscopic ultrasound(EUS) in the assessment of detailed structures of pancreatic cystic neoplasms(PCNs) compared to computed tomography(CT) and magnetic resonance imaging(MRI).METHODS All patients with indeterminate PCNs underwent CT, MRI, and EUS. The detailed information, including size, number, the presence of a papilla/nodule, the presence of a septum, and the morphology of the pancreatic duct of PCNs were compared among the three imaging modalities. The size of each PCN was determined using the largest diameter measured. A cyst consisting of several small cysts was referred to as a motherdaughter cyst. Disagreement among the three imaging modalities regarding the total number of mother cysts resulted in the assumption that the correct number was the one in which the majority of imaging modalities indicated.RESULTS A total of 52 females and 16 males were evaluated. The median size of the cysts was 42.5 mm by EUS, 42.0 mm by CT and 38.0 mm by MRI; there was no significant difference in size as assessed among the three imaging techniques. The diagnostic sensitivity and ability of EUS to classify PCNs were 98.5%(67/68) and 92.6%(63/68), respectively. These percentages were higher than those of CT(73.1%, P < 0.001; 17.1%, P < 0.001) and MRI(81.3%, P = 0.001; 20.3%, P < 0.001). EUS was also able to better assess the number of daughter cysts in mother cysts than CT(P = 0.003); however, there was no significant difference between EUS and MRI in assessing mother-daughter cysts(P = 0.254). The papilla/nodule detection rate by EUS was 35.3%(24/68), much higher than those by CT(5.8%, 3/52) and MRI(6.3%, 4/64). The detection rate of the septum by EUS was 60.3%(41/68), which was higher than those by CT(34.6%, 18/52) and by MRI(46.9%, 30/64); the difference between EUS and CT was significant(P = 0.02). The rate of visualizing the pancreatic duct using EUS was 100%, whereas using CT and MRI it was less than 10%.CONCLUSION EUS helps visualize the detailed structures of PCNs and has many advantages over CT and MRI. EUS is valuable in the diagnosis and assessment of PCNs.

Update on surgical treatment of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential(neurendocrine tumors PNETs) or overt(neuroendocrine carcinomas PNECs) malignant,but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimallyinvasive approaches which should be tailored to the individual patient. Generally,surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs,indications for tumor resection are much wider than for pancreatic adenocarcinoma,in many cases due to the relatively benign tumor biology. Thus,patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands,even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However,poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly singlecenter series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable,ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review,we summarize recent advances in the surgical treatment of PNENs.

Pancreatic intraductal papillary mucinous neoplasms:Current diagnosis and management

Intraductal papillary mucinous neoplasms(IPMNs)represent approximately 1%of all pancreatic neoplasms and 25%of cystic neoplasms.They are divided into three types:main duct-IPMN(MD-IPPMN),branch duct-IPMN(BD-IPMN),and mixed type-IPMN.In this review,diagnostics,including clinical presentation and radiological investigations,were described.Magnetic resonance imaging is the most useful for most IPMNs.Management depends on the type and radiological features of IPMNs.Surgery is recommended for MD-IPMN.For BD-IPMN,management involves surgery or surveillance depending on the tumor size,cyst growth rate,solid components,main duct dilatation,high-grade dysplasia in cytology,the presence of symptoms(jaundice,new-onset diabetes,pancreatitis),and CA 19.9 serum level.The patient’s age and comorbidities should also be taken into consideration.Currently,there are different guidelines regarding the diagnosis and management of IPMNs.In this review,the following guidelines were presented:Sendai International Association of Pancreatology guidelines(2006),American Gastroenterological Association guidelines,revised international consensus Fukuoka guidelines(2012),revised international consensus Fukuoka guidelines(2017),and European evidence-based guidelines according to the European Study Group on Cystic Tumours of the Pancreas(2018).The Verona Evidence-Based Meeting 2020 was also presented and discussed.

Endoscopic ultrasound-guided injective ablative treatment of pancreatic cystic neoplasms

With the development of cross-sectional imaging modalities and the increasing attention being paid to physical examinations, the prevalence of pancreatic cystic neoplasms(PCNs) has increased. PCNs comprise a broad differential spectrum with some PCNs having low or no malignant potential and others having high malignant potential. The morbidity and mortality rates related to major pancreatic surgical resection are high. Long-term surveillance may not only increase the financial burden and psychological stress for patients but also result in a missed malignancy. Minimally invasive endoscopic ultrasound(EUS)-guided ethanol ablation was first reported in 2005. Several other agents, such as paclitaxel, lauromacrogol, and gemcitabine, were reported to be effective and safe for the treatment of PCNs. These ablative agents are injected through a needle inserted into the cyst via transgastric or transduodenal puncture. This treatment method has been substantially developed in the last 15 years and is regarded as a promising treatment to replace surgical resection for PCNs. While several reviews of EUS-guided ablation have been published, no systematic review has evaluated this method from patient preparation to follow-up in detail. In the present review, we systematically describe EUS-guided injective ablation with regard to the indications, contraindications, preoperative treatment, endoscopic procedure, postoperative care and follow-up, evaluation method, treatment efficiency, safety profile, tips and tricks, and current controversies and perspectives.

Intraductal papillary mucinous neoplasms and other pancreatic cystic lesions

Pancreatic cystic neoplasms are being increasingly recognized, even in the absence of symptoms, in large part, due to markedly improved imaging modalities such as magnetic resonance imaging (MRI)/magnetic resonance cholangio pancreatography (MRCP) and computer tomography (CT) scanning. During the past 2 decades, better imaging of these cystic lesions has resulted in definition of different types, including pancreatic intraductal papillary mucinous neoplasms (IPMN). While IPMN represent only a distinct minority of all pancreatic cancers, they appear to be a relatively frequent neoplastic form of pancreatic cystic neoplasm. Moreover, IPMN have a much better outcome and prognosis compared to pancreatic ductal adenocarcinomas. Therefore, recognition of this entity is exceedingly important for the clinician involved in diagnosis and further evaluation of a potentially curable form of pancreatic cancer.

Resection of pancreatic cystic neoplasms in recurrent acute pancreatitis prevents recurrent pancreatitis but does not identify more malignancies

BACKGROUND Recurrent acute pancreatitis(RAP)may be a presenting feature of and an indication for resection of pancreatic cysts,including intra-ductal papillary mucinous neoplasm(IPMN).Few data are available regarding the prevalence of malignancy and post-operative RAP in this population.AIM To study the role of resection to help prevent RAP and analyze if presentation as RAP would be a predictor for malignancy.METHODS This retrospective study assessed 172 patients who underwent surgical resection of pancreatic cystic neoplasms at a university hospital between 2002 and 2016.The prevalence of preoperative high-risk cyst features,and of neoplasia was compared between patients with and without RAP.To identify the cause of pancreatitis,all the patients had a detailed history of alcohol,smoking,medications obtained,and had cross-sectional imaging(contrast-enhanced computed tomography/magnetic resonance imaging)and endoscopic ultrasound to look for gallstone etiology and other structural causes for pancreatitis.The incidence of RAP post-resection was the primary outcome.RESULTS IPMN accounted for 101 cases(58.7%){[branch duct(BD)59(34.3%),main duct(MD)42](24.4%)}.Twenty-nine(16.9%)presented with RAP(mean 2.2 episodes):15 had BD-IPMN,8 MD-IPMN,5 mucinous cystic neoplasm and 1 serous cystic neoplasm.Malignancy was similar among those with vs without RAP for all patients[6/29(20.7%)vs 24/143(16.8%)]and IPMN patients[6/23(26.1%)vs 23/78(29.5%)],although tended to be higher with RAP in BD-IPMN,[5/15(33.3%)vs 3/44(6.8%),P=0.04].At mean follow-up of 7.2 years,1(3.4%)RAP patient had post-resection RAP.The mean episodes of acute pancreatitis before vs after surgery were 3.4 vs 0.02(P<0.0001).CONCLUSION Malignancy was not increased in patients with pancreatic cystic neoplasms who have RAP compared to those without RAP.In addition,specific cyst characteristics were not clearly associated with RAP.The incidence of RAP was markedly decreased in almost all patients following cyst resection.

A new combined criterion to better predict malignant lesions in patients with pancreatic cystic neoplasms

Objective:Cystic lesions of the pancreas have been increasingly recognized.Some lesions exhibit benign behavior,while others have unequivocal malignant potential.Thus,accurate identification of malignancy in patients diagnosed with pancreatic cystic neoplasms(PCNs)remains a major challenge.The aim of this study was to define a combined criterion to better predict malignant lesions in patients with PCNs.Methods:We retrospectively analyzed 165 patients who underwent resection of PCNs from October 2011 to May 2017.The relationship among malignancy and serum carbohydrate antigen 19-9(CA19-9),preoperative neutrophil-to-lymphocyte ratio(NLR),and the presence of enhanced solid component on imaging was analyzed.Results:NLR before surgery in patients with malignant PCNs(2.81±2.14)was significantly higher than that in patients diagnosed with pancreatic neuroendocrine tumor(1.90±0.69,P=0.013)or healthy volunteers(1.40±0.48;P<0.001).Serum CA19-9≥39U/m L,NLR>1.976 and presence of enhanced solid component were independent predictors of PCN malignancy.A combined criterion meeting any two or more of the three elements including CA19-9≥39 U/m L,NLR>1.976,and presence of enhanced solid component on computed tomography imaging is an indicator with a high positive predictive value of 80.5%and a high negative predictive value of 87.9%,and thus,represents a highly accurate test(86.1%).Conclusions:The new combined criterion is an effective predictor of tumor malignancy in patients with PCNs.

Advances in medical treatment for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PanNENs)are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years.For patients with locally advanced or distant metastatic PanNENs,systemic treatment options vary due to the different differentiations,grades and stages.The available options for systemic therapy include somatostatin analogs,molecularly targeted agents,cytotoxic chemotherapeutic agents,immune checkpoint inhibitors,and peptide receptor radionuclide therapy.In addition,the development of novel molecularly targeted agents is currently in progress.The sequence of selection between different chemotherapy regimens has been of great interest,and resistance to chemotherapeutic agents is the major limitation in their clinical application.Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents.Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors,and greater therapeutic efficacy may be achieved by emerging radiolabeled peptides.Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity,dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy.Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments.In the future,the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.

Correlation between radiologic features on contrastenhanced CT and pathological tumor grades in pancreatic neuroendocrine neoplasms

Contrast-enhanced computed tomography(CT)contributes to the increasing detection of pancreatic neuroendocrine neoplasms(PNENs).Nevertheless,its value for differentiating pathological tumor grades is not well recognized.In this report,we have conducted a retrospective study on the relationship between the 2017 World Health Organization(WHO)classification and CT imaging features in 94 patients.Most of the investigated features eventually provided statistically significant indicators for discerning PNENs G3 from PNENs G1/G2,including tumor size,shape,margin,heterogeneity,intratumoral blood vessels,vascular invasion,enhancement pattern in both contrast phases,enhancement degree in both phases,tumor-to-pancreas contrast ratio in both phases,common bile duct dilatation,lymph node metastases,and liver metastases.Ill-defined tumor margin was an independent predictor for PNENs G3 with the highest area under the curve(AUC)of 0.906 in the multivariable logistic regression and receiver operating characteristic curve analysis.The portal enhancement ratio(PER)was shown the highest AUC of 0.855 in terms of quantitative features.Our data suggest that the traditional contrastenhanced CT still plays a vital role in differentiation of tumor grades and heterogeneity analysis prior to treatment.

Endoscopic ultrasound in the diagnosis of pancreatic intraductal papillary mucinous neoplasms

Pancreatic cystic lesions are increasingly recognised due to the widespread use of different imaging modalities.Intraductal papillary mucinous neoplasms(IPMNs)of the pancreas represent a common,but also heterogeneous group of cystic tumors with a significant malignant potential.These neoplasms must be differentiated from other cystic tumors and properly classified into their different types,main-duct IPMNs vs branchduct IPMNs.These types have a different malignant potential and therefore,different treatment strategies need to be implemented.Endoscopic ultrasound(EUS)offers the highest resolution of the pancreas and can aid in the differential diagnosis,classification and differentiation between benign and malignant tumors.The addition of EUS fine-needle aspiration can supply further information by obtaining fluid for cytology,measurement of tumor markers and perhaps DNA analysis.Novel techniques,such as the use of contrast and sophisticated equipment,like intraductal probes can provide information regarding malignant features and extent of these neoplasms.Thus,EUS is a valuable tool in the diagnosis and appropriate management of these tumors.

Preoperative ultrasound combined with routine blood tests in predicting the malignant risk of pancreatic cystic neoplasms

Objective:Accurate preoperative identification of benign or malignant pancreatic cystic neoplasms(PCN)may help clinicians make better intervention choices and will be essential for individualized treatment.Methods:Preoperative ultrasound and laboratory examination findings,and demographic characteristics were collected from patients.Multiple logistic regression was used to identify independent risk factors associated with malignant PCN,which were then included in the nomogram and validated with an external cohort.The Net Reclassification Index(NRI)and Integrated Discrimination Improvement(IDI)were calculated to evaluate the improvement in the predictive power of the new model with respect to that of a combined imaging and tumor marker prediction model.Results:Malignant PCN were found in 83(40.7%)and 33(38.7%)of the model and validation cohorts,respectively.Multivariate analysis identified age,tumor location,imaging of tumor boundary,blood type,mean hemoglobin concentration,neutrophil-tolymphocyte ratio,carbohydrate antigen 19-9,and carcinoembryonic antigen as independent risk factors for malignant PCN.The calibration curve indicated that the predictions based on the nomogram were in excellent agreement with the actual observations.A nomogram score cutoff of 192.5 classified patients as having low vs.high risk of malignant PCN.The model achieved good C-statistics of 0.929(95%CI 0.890–0.968,P<0.05)and 0.951(95%CI 0.903–0.998,P<0.05)in predicting malignancy in the development and validation cohorts,respectively.NRI=0.268;IDI=0.271(P<0.001 for improvement).The DCA curve indicated that our model yielded greater clinical benefits than the comparator model.Conclusions:The nomogram showed excellent performance in predicting malignant PCN and may help surgeons select patients for detailed examination and surgery.The nomogram is freely available at https://wangjunjinnomogram.shinyapps.io/DynNomapp/.

Online calculator for predicting the risk of malignancy in patients with pancreatic cystic neoplasms: A multicenter, retrospective study

BACKGROUND Efficient and practical methods for predicting the risk of malignancy in patients with pancreatic cystic neoplasms(PCNs)are lacking.AIM To establish a nomogram-based online calculator for predicting the risk of malignancy in patients with PCNs.METHODS In this study,the clinicopathological data of target patients in three medical centers were analyzed.The independent sample t-test,Mann–Whitney U test or chi-squared test were used as appropriate for statistical analysis.After univariable and multivariable logistic regression analysis,five independent factors were screened and incorporated to develop a calculator for predicting the risk of malignancy.Finally,the concordance index(C-index),calibration,area under the curve,decision curve analysis and clinical impact curves were used to evaluate the performance of the calculator.RESULTS Enhanced mural nodules[odds ratio(OR):4.314;95%confidence interval(CI):1.618–11.503,P=0.003],tumor diameter≥40 mm(OR:3.514;95%CI:1.138–10.849,P=0.029),main pancreatic duct dilatation(OR:3.267;95%CI:1.230–8.678,P=0.018),preoperative neutrophil-to-lymphocyte ratio≥2.288(OR:2.702;95%CI:1.008–7.244,P=0.048],and preoperative serum CA19-9 concentration≥34 U/mL(OR:3.267;95%CI:1.274–13.007,P=0.018)were independent risk factors for a high risk of malignancy in patients with PCNs.In the training cohort,the nomogram achieved a C-index of 0.824 for predicting the risk of malignancy.The predictive ability of the model was then validated in an external cohort(C-index:0.893).Compared with the risk factors identified in the relevant guidelines,the current model showed better predictive performance and clinical utility.CONCLUSION The calculator demonstrates optimal predictive performance for identifying the risk of malignancy,potentially yielding a personalized method for patient selection and decision-making in clinical practice.

Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms

BACKGROUND Although PNENs generally have a better prognosis than pancreatic cancers,some PNENs display malignant behavior including lymph node(LN)metastasis.Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs.However,the indications for LN dissection are still controversial.Over the last decade,minimally invasive surgery such as laparoscopic pancreatic surgery(LPS)has been increasingly performed for pancreatic tumors including PNENs.AIM To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS.METHODS From April 2001 to December 2019,92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital.Finally,82 patients were enrolled in this study.Using perioperative factors,we examined the predictive factors for LN metastasis in PNENs.RESULTS Among the 82 patients,the percentage of LN metastasis according to the pathological findings was 12%(10/82 cases).The median tumor size was 12 mm(range:5-90 mm).The median tumor size in the LN-positive group(37 mm)was significantly larger than that in the LN-negative group(12 mm)(P=0.0001).Multivariate analyses revealed that larger tumor size(≥20 mm)was an independent risk factor for LN metastasis(odds ratio 16.8,P=0.0062).In patients with small tumors(≤10 mm),LN metastasis was not found.CONCLUSION Larger tumor size(≥20 mm)is an independent risk factor for LN metastasis in PNENs.In smaller PNENs(≤10 mm),we may be able to choose limited surgery without LN dissection.

Pancreatic Neuroendocrine Neoplasms: Correlation between MR Features and Pathological Tumor Grades

This study investigated the accuracy of MRI features in differentiating the pathological grades of pancreatic neuroendocrine neoplasms（PNENs）. A total of 31 PNENs patients were retrospectively evaluated, including 19 cases in grade 1, 5 in grade 2, and 7 in grade 3. Plain and contrastenhanced MRI was performed on all patients. MRI features including tumor size, margin, signal intensity, enhancement patterns, degenerative changes, duct dilatation and metastasis were analyzed. Chi square tests, Fisher＇s exact tests, one-way ANOVA and ROC analysis were conducted to assess the associations between MRI features and different tumor grades. It was found that patients with older age, tumors with higher TNM stage and without hormonal syndrome had higher grade of PNETs（all P〈0.05）. Tumor size, shape, margin and growth pattern, tumor pattern, pancreatic and bile duct dilatation and presence of lymphatic and distant metastasis as well as MR enhancement pattern and tumor-topancreas contrast during arterial phase were the key features differentiating tumors of all grades（all P〈0.05）. ROC analysis revealed that the tumor size with threshold of 2.8 cm, irregular shape, pancreatic duct dilatation and lymphadenopathy showed satisfactory sensitivity and specificity in distinguishing grade 3 from grade 1 and grade 2 tumors. Features of peripancreatic tissue or vascular invasion, and distant metastasis showed high specificity but relatively low sensitivity. In conclusion, larger size, poorlydefined margin, heterogeneous enhanced pattern during arterial phase, duct dilatation and the presence of metastases are common features of higher grade PNENs. Plain and contrast-enhanced MRI provides the ability to differentiate tumors with different pathological grades.

High-grade pancreatic intraepithelial neoplasia diagnosed based on changes in magnetic resonance cholangiopancreatography findings:A case report

BACKGROUND High-grade pancreatic intraepithelial neoplasia(PanIN)exhibits no mass and is not detected by any examination modalities.However,it can be diagnosed by pancreatic juice cytology from indirect findings.Most previous cases were diagnosed based on findings of a focal stricture of the main pancreatic duct(MPD)and caudal MPD dilatation and subsequent pancreatic juice cytology using endoscopic retrograde cholangiopancreatography(ERCP).We experienced a case of high-grade PanIN with an unclear MPD over a 20-mm range,but without caudal MPD dilatation on magnetic resonance cholangiopancreatography(MRCP).CASE SUMMARY A 60-year-old female patient underwent computed tomography for a follow-up of uterine cancer post-excision,which revealed pancreatic cysts.MRCP revealed an unclear MPD of the pancreatic body at a 20-mm length without caudal MPD dilatation.Thus,course observation was performed.After 24 mo,MRCP revealed an increased caudal MPD caliber and a larger pancreatic cyst.We performed ERCP and detected atypical cells suspected of adenocarcinoma by serial pancreatic juice aspiration cytology examination.We performed a distal pancreatectomy and obtained a histopathological diagnosis of high-grade PanIN.Pancreatic parenchyma invasion was not observed,and curative resection was achieved.CONCLUSION High-grade Pan-IN may cause MPD narrowing in a long range without caudal MPD dilatation.

Predictive factors associated with malignancy of intraductal papillary mucinous pancreatic neoplasms

AIM:To identify preoperative predictive factors associated with malignancy of intraductal papillary mucinous neoplasms(IPMNs) of the pancreas.METHODS:Between April 1995 and April 2010,129 patients underwent surgical resection for IPMNs at our institute and had confirmed pathologic diagnoses.The medical records were retrospectively reviewed and immunohistochemical staining for mucin(MUC) in pancreatic tissues was performed.RESULTS:Univariate analysis showed that the following five variables were closely associated with malignant IPMNs preoperatively:absence of extrapancreatic malignancy;symptoms;tumor size > 4 cm;main pancreaticduct(MPD) size > 7 mm;and lymph node enlargement on preoperative computed tomography(CT).Multivariate analysis revealed that the following two factors were significantly associated with malignant IPMNs preoperatively:MPD size > 7 mm [odds ratio(OR) = 2.50];and lymph node enlargement on preoperative CT(OR = 3.57).No significant differences in the expression of MUC1,MUC2 and MUC5AC were observed between benign and malignant IPMNs.CONCLUSION:MPD size > 7 mm and preoperative lymph node enlargement on CT are useful predictive factors associated with malignancy of IPMNs.

EUS for pancreatic cystic neoplasms: The roadmap to the future is much more than just a few shades of gray

Pancreatic cystic and neoplasms are being diagnosed with increasing frequency. Accurate diagnosis and determination of benign versus malignant lesions is crucial for determining need for surveillance versus surgery or endoscopic therapy as well as avoiding unnecessary surgery in cysts with no malignant potential. Tumor markers such as KRAS and GNAS hold promise, but which molecular marker or a combination of markers is most useful and cost effective remains to be seen. Advanced imaging with confocal laser endomicroscopy can serve as an optical biopsy and play a part in the diagnostic algorithm. Microforceps aided biopsy of pancreatic cyst wall and tumor contents hold great promise as they allow direct tissue acquisition. Much progress has been made in the role of EUS guided evaluation of pancreatic cystic neoplasms over the last several years, and with the advances enumerated above, the future is more than just a few shades of grey. Future studies should include prospective multiarm trials of microforceps biopsy versus conventional EUS-FNA and use of biochemical and molecular markers, confocal laser endomicroscopy or a combination thereof to determine best approach to pancreatic cystic neoplasms. In Osler's words, ‘Medicine is a science of uncertainty and an art of probability'. Incorporation of advanced imaging and molecular markers into a new diagnostic algorithm with subsequent validation through retrospective and prospective studies has the potential to increase diagnostic accuracy and guide optimal management of patients and improve outcomes.

Methylation changes at the GNAS imprinted locus in pancreatic cystic neoplasms are important for the diagnosis of malignant cysts

BACKGROUND Guanine nucleotide-binding protein,alpha stimulating(GNAS)mutations are characteristic of intraductal papillary mucinous neoplasms(IPMNs).Pancreatic ductal adenocarcinomas(PDACs)harboring GNAS mutations originate in IPMNs.GNAS is a complex imprinted locus that produces five transcripts regulated by differential methylated regions,NESP55,GNASAS,GNASXL,GNAS1A,and GNAS.AIM To evaluate if methylation changes in the differential methylated regions of GNAS locus contributed to malignant progression of pancreatic cysts.METHODS GNAS locus methylation was analyzed in archival pancreatic cyst fluid(PCF)obtained by endoscopic ultrasound with fine-needle aspiration by methylation specific–multiplex ligation dependent probe amplification.Results were normalized and analyzed using Coffalyser.Net software.RESULTS Fifty-two PCF samples obtained by endoscopic ultrasound with fine-needle aspiration and previously characterized for KRAS and GNAS mutations were studied.The final diagnoses were surgical(11)and clinicopathological(41),including 30 benign cysts,14 pre-malignant cyst,and eight malignant cysts.Methylation changes at NESP55,GNASAS,GNAS1A,and especially GNASXL were more frequent in malignant cysts,and NESP55 and GNASAS were useful for diagnosis.A combined variable defined as“GNAS locus methylation changes”was significantly associated with malignancy(6/8 malignant cysts and only 2/20 benign cysts)and improved classification.Hypermethylation in both maternally(NESP55)and paternally(GNASXL)derived promoters was found in 3/3 PDACs.CONCLUSION This is the first study to identify methylation changes in the GNAS locus,improving the diagnosis of malignant pancreatic cysts and suggesting a role in progression to PDAC.

Surgical management of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex nature and pathophysiological behaviour,surgical management continues to evolve.Surgery remains the cornerstone of treatment for most non-functional and functional pancreatic neuroendocrine tumours,while lymphadenectomy remains a controversial subject.Different techniques,such as pancreas-preserving and minimally invasive approaches,continue to evolve and offer the same overall outcomes as open surgery.This comprehensive review describes in detail the current and most up-todate classification and staging of pancreatic neuroendocrine tumours,explores the rationale for nonsurgical and surgical management,and focuses on surgical treatment and more specifically,on minimally invasive approaches.