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Objective: Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas., Summary of Background Data: Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4)., Methods: This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms., Results: Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5., Conclusions: This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice., Competing Interests: The authors report no conflicts of interest, (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pancreatic cystic lesions (PCLs) are increasingly found on cross-sectional imaging, with the majority having a low risk for malignancy. The added value of fine-needle aspiration (FNA) in risk stratification remains unclear. We evaluated the impact of three FNA needles on diagnostic accuracy, clinical management, and the ability to accrue fluid for tumor markers., Methods: A multicenter prospective trial randomized 250 patients with PCLs ≥ 13 mm 2:1:1 to 19G Flex, 19G, and 22G needles with crossover for repeated FNA procedures. Diagnostic accuracy was established at 2-year follow-up, with the final diagnosis from surgical histopathology or consensus diagnosis by experts based sequentially on clinical presentation, imaging, and aspirate analysis in blinded review., Results: Enrolled patients (36 % symptomatic) had PCLs in the head (44 %), body (28 %), and tail (26 %). Percentage of cyst volume aspirated was 78 % (72 % - 84 %) for 19G Flex, 74 % (64 % - 84 %) for 22G, and 73 % (63 % - 83 %) for 19G ( P  = 0.84). Successful FNA was significantly higher for 19G Flex (89 % [82 % - 94 %]) and 22G (82 % [70 % - 90 %]) compared with 19G (75 % [63 % - 85 %]) ( P  = 0.02). Repeated FNA was required more frequently in head/uncinate lesions than in body and tail ( P  < 0.01). Diagnostic accuracy of the cyst aspirate was 84 % (73 % - 91 %) against histopathology at 2-year follow-up (n = 79), and 77 % (70 % - 83 %) against consensus diagnosis among nonsurgical cases (n = 171). Related serious adverse events occurred in 1.2 % (0.2 % - 3.5 %) of patients., Conclusions: Our study results demonstrate a statistically significant difference among the three needles in the overall success rate for aspiration, but not in the percentage of cyst volume aspirated. Flexible needles may be particularly valuable in sampling cystic PCLs in the pancreatic head/uncinate process., Competing Interests: Dr. Al-Haddad has received consulting fees from Boston Scientific Corporation and Takeda Pharmaceuticals. Dr. Wallace has consulting relationships with Cosmo/Aries Pharmaceuticals, Anx Robotica, Covidien, GI Supply, Endokey, Endostart, and Microtek, holds stock with Virgo Inc., and has received research grants from Boston Scientific Corporation, Fujifilm, Olympus, Medtronic, and NinePoint Medical. Dr. Sethi has consulting relationships with Boston Scientific Corporation, Olympus, and FUJIFILM. Dr. Pleskow has consulting relationships with Boston Scientific Corporation, Medtronic, Olympus, Fujifilm, and NinePoint Medical. Dr. Pannala has consulting relationships with HCL America and has received general payments from Boston Scientific Corporation, Apollo Endosurgery, Abbvie, and Olympus America. Dr. DeWitt has consulting relationships with Boston Scientific Corporation and has received research grant support from Concordia Laboratories Inc. and Vyaire Medical, Inc. Dr. Faigel has received research support from Boston Scientific Corporation. The remaining authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background & Aims: The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients., Methods: We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers., Results: We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%., Conclusions: We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to critically analyze the safety of the revised guidelines, with focus on cyst size and worrisome features in the management of BD-IPMN., Background: The Sendai guidelines for management of branch duct (BD) intraductal papillary mucinous neoplasm (IPMN) espouse safety of observation of asymptomatic cysts smaller than 3 cm without nodules (Sendai negative). Revised international consensus guidelines published in 2012 suggest a still more conservative approach, even for lesions of 3 cm or larger. By contrast, 2 recent studies have challenged the safety of both guidelines, describing invasive carcinoma or carcinoma in situ in 67% of BD-IPMN smaller than 3 cm and in 25% of "Sendai-negative" BD-IPMN., Methods and Results: Review of a prospective database identified 563 patients with BD-IPMN. A total of 240 patients underwent surgical resection (152 at the time of diagnosis and 88 after being initially followed); the remaining 323 have been managed by observation with median follow-up of 60 months. No patient developed unresectable BD-IPMN carcinoma during follow-up. Invasive cancer arising in BD-IPMN was found in 23 patients of the entire cohort (4%), and an additional 21 patients (3.7%) had or developed concurrent pancreatic ductal adenocarcinoma. According to the revised guidelines, 76% of resected BD-IPMN with carcinoma in situ and 95% of resected BD-IPMN with invasive cancer had high-risk stigmata or worrisome features. The risk of high-grade dysplasia in nonworrisome lesions smaller than 3 cm was 6.5%, but when the threshold was raised to greater than 3 cm, it was 8.8%, and 1 case of invasive carcinoma was found., Conclusions: Expectant management of BD-IPMN following the old guidelines is safe, whereas caution is advised for larger lesions, even in the absence of worrisome features.

Preoperative diagnosis of pancreatic cysts benefits from integrating the clinical, radiological, and cytological features. As patient management algorithms evolve to increasingly nonsurgical options, accuracy in distinguishing mucinous from nonmucinous and benign from malignant mucinous cysts is important. This review focuses on pseudocysts, serous cystadenomas, intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Patients with pseudocysts almost always present with pancreatitis and are usually medically managed. Radiological studies reveal a unilocular cyst mostly in the pancreatic tail. Cyst fluid is thin, with high amylase but low carcinoembryonic antigen (CEA) levels. DNA mutations are absent. Serous cystadenomas are benign and do not require resection. Patients are usually asymptomatic and have microcystic or macrocystic masses anywhere in the pancreas. Cytology is frequently nondiagnostic. CEA and amylase levels are low. DNA analysis may reveal loss of heterozygosity (LOH) at 3p if associated with Von Hippel-Lindau disease. Neoplastic mucinous cysts are highly variable in their presentation. Most are resected. Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged women and demonstrate a septated cyst without dilatation of the main pancreatic duct. Branch duct IPMNs are more common in the pancreatic head of elderly men. Main duct dilatation correlates with main duct or combined type IPMN. Both types of mucinous cysts produce variable amounts of mucin. Cytologically nonmalignant but atypical epithelial cells, even when scant, are an indication of a high risk for malignancy. High CEA level supports a mucinous cyst, as do KRAS mutation and good quality DNA levels. KRAS mutation and multiple LOH support malignancy., ((c) 2009 American Cancer Society.)

Background: Despite advances in cross-sectional imaging and the use of molecular markers, distinguishing between benign and malignant cysts remains a clinical challenge., Aims: To identify both preoperative clinical and cyst characteristics at the time of EUS that predict malignancy., Methods: A retrospective analysis was performed on consecutive patients with pancreatic cysts who underwent endoscopic ultrasound (EUS) and surgical resection from May 1996 to December 2007 at a tertiary centre. Clinical history, EUS characteristics, cytology, tumour markers and surgical histology were collected. Predictors of malignancy were determined by univariate and multivariate analysis using logistic regression., Results: A total of 153 patients underwent a EUS and subsequent surgical intervention.Of the 153 patients, 57 (37%) had a histological diagnosis of malignancy. On univariate analysis, older age (P < 0.001), male gender (P = 0.010), jaundice (P = 0.039), history of other malignancy (P = 0.036), associated mass in cyst (P = 0.004) and malignant cytology (P < 0.001) were found to be associated with malignancy. History of pancreatitis (P = 0.008) and endoscopist impression of pseudocyst (P = 0.001) were found to be associated with benign cysts. Multivariate analysis found that only older age [Odds ratio (OR), 1.04; 95% confidence interval (CI), 1.01-1.08], male gender (OR, 2.26; 95% CI, 1.08-4.73) and malignant cytology (OR, 6.60; 95% CI, 2.02-21.58) were independent predictors of malignancy., Conclusions: Older age, male gender and malignant cytology from EUS predict malignancy at surgical resection. These characteristics may be used to estimate the probability of malignancy in a cyst and aid in management.

The management of pancreatic cystic lesions offers a challenge to clinicians. Mucinous cystic lesions pose a low risk of the development of neoplasia that must be taken into account in long-term management. Although the natural history has not been well defined, it is likely that malignant change in the mucinous epithelium takes place over years, very similar to what is observed with Barrett's esophagus. The traditional therapy of mucinous cystic lesions has been surgical resection. Lesions in the head of the pancreas will require a Whipple resection whereas tail lesions are managed with a distal pancreatectomy and splenectomy. In patients at high risk for surgical resection, the risk/benefit ratio may be excessively high, not supporting the use of resection therapy. Ethanol ablation therapy has been thoroughly studied in hepatic, renal, and thyroid cysts. Epithelial ablation with ethanol appears to be highly effective and relatively safe. Recently, ethanol ablation has been evaluated in pancreatic cystic neoplasms. In macrocystic lesions between 1 and 5 cm, ethanol lavage will result in epithelial ablation and cyst resolution in a high percentage of patients. Pancreatitis is rarely observed clinically and is not present in resection specimens. A randomised prospective clinical trial is currently underway.

The diagnosis and management of pancreatic cystic lesions is a common problem. At least 1% of hospitalized patients at major medical centers will have a pancreatic cystic lesion on cross sectional imaging. Up to a quarter of all pancreata examined in an autopsy series contained a pancreatic cyst, 16% of which were lined by an "atypical" epithelium and 3% of which had progressed to carcinoma-in-situ (high grade dysplasia). in the past, it was thought these cystic lesions were benign, but increasing evidence points to the cystic lesions as being the origin of some pancreatic malignancies. The most important clinical tools in the diagnosis and management of pancreatic cystic lesions are cross sectional imaging, endoscopic ultrasound, and cyst fluid analysis. The most important differential diagnosis is distinguishing mucinous (pre-malignant) and non-mucinous cystic lesions. The findings of a macrocystic lesion containing viscous fluid rich in CEA are supportive of a diagnosis of a mucinous lesion. Serous lesion are the most common non-mucinous cyst and are characterized by a microcystic morphology, non-viscous fluid and a low concentration of CEA in the cyst fluid. The following document includes a description of neoplastic pancreatic cysts, a critical review of relevant diagnostic tests, and a discussion of treatment options. We have proposed a set of guidelines for the diagnosis and management of patients with neoplastic pancreatic cysts. The guidelines are based on published data backed by an analysis of the quality of the data and are designed to address the most frequent and important clinical scenarios. In addition to providing a summary of the diagnostic data, we offer diagnostic and management suggestions based on 13 common clinical problems. Although the field is rapidly evolving, a set of core principles is provided based on a balance between the risk of malignancy and the benefit of pancreatic resection.

Background: EUS can provide detailed imaging of pancreatic malignancies and direct fine needle aspiration (FNA) of pancreatic masses. The ability of EUS to detect and stage malignancy in cystic and intraductal lesions has not been investigated. Our aim was to determine the sensitivity and specificity of EUS imaging and FNA in detecting and staging of malignancy in solid, cystic, and intraductal lesions of the pancreas., Methods: The records of 96 patients (46 solid, 26 cystic, 24 intraductal lesions) who underwent EUS followed by surgical exploration over a 3-year period were reviewed. The accuracy of EUS for detecting and staging malignancy was calculated based on the results of surgery and histology., Results: EUS-guided FNA provided evidence of malignancy in solid, cystic, and ductal lesions with sensitivities of 59.5%, 50%, and 60%, respectively. The accuracy of staging by EUS was significantly less for intraductal lesions (47%), compared with cystic (100%) and solid lesions (85%) (p < 0. 05)., Conclusions: EUS can be used to detect malignancy in cystic and intraductal tumors of the pancreas.

Background: Cystic tumors of the pancreas are composed of benign, premalignant, malignant, and inflammatory lesions that are traditionally difficult to diagnose. Most of the tumors are initially detected on CT/US scanning, but often the morphological characteristics are insufficient for making a definitive diagnosis. Endoscopic ultrasound (EUS) may be an ideal tool for imaging of these lesions because it can provide highly detailed imaging without interference by bowel or air. Furthermore, EUS can direct fine needle aspiration of the lesions, providing cyst fluid for cytologic examination. The findings of cyst fluid cytology can be complemented by the use of cyst fluid tumor makers such as CEA. Using the morphologic appearance by endosonography, the results of cytology, and tumor marker analysis, EUS can often differentiate between benign, malignant, and inflammatory cystic lesions of the pancreas.