Neutrophil Gelatinase-Associated Lipocalin for the Differentiation of Mucinous Pancreatic Cystic Lesions.

Undetermined pancreatic cystic lesion (PCL) differentiation benefits from endoscopic ultrasound (EUS) based on morphology and cyst fluid analysis, but room for new biomarkers exists. Our aim was to assess the intracystic and serum diagnostic value of neutrophil gelatinase-associated lipocalin (Ngal) and interleukin 1 beta (IL-1ß) for differentiation of PCLs. This prospective study included patients from one tertiary hospital, evaluated between April 2018 and May 2020. EUS fine-needle aspiration or pancreatic pseudocysts drainage was the source of PCL intracystic liquid. The final diagnosis was based on surgery or EUS results (morphology, cytology, glucose, and CEA-carcinoembryogenic antigen). The intracystic samples were tested for Ngal, IL-1ß, glucose, and CEA, and serum for Ngal and IL-1ß. We evaluated 63 cysts, 33 pseudocysts, and 30 non-inflammatory cysts. The diagnostic sensitivity and specificity for mucinous PCL was 70.8% and 92.3% for intracystic Ngal (cut-off: 500-800 ng/dL), without correlation with serum Ngal, no matter the inclusion of infected pseudocysts. After exclusion of infected pseudocysts, the sensitivity and specificity for glucose were 87% and 75%, respectively, and for CEA, they were 87.1%, and 96.8%, respectively. Intracystic Ngal shows promise in differentiating mucinous PCLs, but researchers need to conduct further studies to confirm its effectiveness. Intracystic IL-1ß and serum Ngal made no diagnostic contribution.

Performance of Intracystic Glucose Measurement for the Characterization of Pancreatic Cystic Lesions.

BACKGROUND AND AIMS: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is essential for the classification of pancreatic cystic lesions (PCLs). Recently, intracystic glucose has been suggested as an alternative to carcinoembryonic antigen (CEA) level as a predictor of mucinous cystic lesions (M-PCLs). This study aims to evaluate the diagnostic performance of intra-cystic glucose in distinguishing between M-PCLs and non M-PCLs (NM-PCLs) and to analyze the possibility of on-site glucose measurement with a standard glucometer. METHODS: Patients with PCLs submitted to EUS-FNA with simultaneous intracystic glucose measurement between 2017 and 2022 were included. The diagnostic performance of glucose versus CEA for the differentiation between M-PCLs and NM-PCLs was compared to a final diagnosis based on the analysis of surgical specimen, intracystic biopsy or, if this data was unavailable, multidisciplinary evaluation. A cut-off of <50 mg/dL was used for the diagnosis of MCLs. Additionally, the agreement between on-site glucose determination with a standard glucometer and laboratory glucose measurement was assessed. RESULTS: Mucinous lesions accounted for 56% of all PCLs. The median values of glucose and CEA for M-PCLs were 18 mg/dL and 286 ng/mL, respectively. Intracystic glucose had a sensitivity and specificity of 93.2% and 76.5%, respectively, for the diagnosis of MCLs (versus 55.6% and 87.5%, respectively, for CEA). The area under the curve was 0.870 for on-site glucose (versus 0.806 for CEA). An excellent correlation was observed between on-site and laboratory glucose measurement (ρ=0.919). CONCLUSIONS: The measurement of intracystic glucose showed superior performance compared with CEA in distinguishing between M-PCLs and NM-PCLs, with excellent correlation between on-site and conventional lab glucose measurement. Thus, on-site intracystic glucose appears to be an excellent biomarker for the characterization of PCLs due to its low cost, high availability, and the need for a minimal cyst fluid volume for its determination.

[A Case of Lymphoepithelial Cyst of the Pancreas for Which Malignancy Could Not Be Ruled Out Difficult Preoperative Diagnosis].

Lymphoepithelial cyst(LEC)of the pancreas is a relatively rare benign cystic disease of the pancreas. In this report, we describe a case of LEC in which a malignant tumor could not be ruled out by preoperative diagnosis and surgery was performed. The patient was a 72-year-old man. A simple CT scan of the chest and abdomen performed as a follow-up for another disease incidentally revealed a mass in the pancreatic tail. Enhanced CT of the abdomen showed a tumor approximately 3 cm in size at the pancreatic tail with no contrast effect. MRCP showed moderate signal on T2WI, high signal on T1WI, and high signal on T2WI on some cysts inside the pancreas. PET-CT showed slight uptake of FDG. Both tumor markers CEA and CA19-9 were normal. Therefore, malignant disease such as pancreatic IPMC could not be ruled out, and laparoscopic distal pancreatectomy plus splenectomy was performed. The pathology results showed a diagnosis of pancreatic lymphoepithelial cyst with slight differentiation into sebaceous gland.

Pancreatic Cysts Greater Than 1 cm Are Associated With an Increased Risk for Developing Pancreatic Cancer in Individuals From Pancreatic-Cancer Prone Kindreds Undergoing Surveillance.

BACKGROUND: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance. METHODS: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging. RESULTS: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion. CONCLUSIONS: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion.

Natural history and growth prediction model of pancreatic serous cystic neoplasms.

OBJECTIVE: Serous cystic neoplasms (SCN) are benign pancreatic cystic neoplasms that may require resection based on local complications and rate of growth. We aimed to develop a predictive model for the growth curve of SCNs to aid in the clinical decision making of determining need for surgical resection. METHODS: Utilizing a prospectively maintained pancreatic cyst database from a single institution, patients with SCNs were identified. Diagnosis confirmation included imaging, cyst aspiration, pathology, or expert opinion. Cyst size diameter was measured by radiology or surgery. Patients with interval imaging ≥3 months from diagnosis were included. Flexible restricted cubic splines were utilized for modeling of non-linearities in time and previous measurements. Model fitting and analysis were performed using R (V3.50, Vienna, Austria) with the rms package. RESULTS: Among 203 eligible patients from 1998 to 2021, the mean initial cyst size was 31 mm (range 5-160 mm), with a mean follow-up of 72 months (range 3-266 months). The model effectively captured the non-linear relationship between cyst size and time, with both time and previous cyst size (not initial cyst size) significantly predicting current cyst growth (p < 0.01). The root mean square error for overall prediction was 10.74. Validation through bootstrapping demonstrated consistent performance, particularly for shorter follow-up intervals. CONCLUSION: SCNs typically have a similar growth rate regardless of initial size. An accurate predictive model can be used to identify rapidly growing outliers that may warrant surgical intervention, and this free model (https://riskcalc.org/SerousCystadenomaSize/) can be incorporated in the electronic medical record.

Diagnosis and management of pancreatic cystic lesions for the non-gastroenterologist.

Although most pancreatic cystic lesions do not progress to cancer, they create concern for patients and their primary care physicians. The lack of consensus guidelines on diagnosis and surveillance of these lesions can lead to a management conundrum. We review current guidelines on diagnosis and management.

[Histopathologic diagnosis of solid and cystic pancreatic lesions with a focus on ductal adenocarcinoma : A vademecum for daily practice]. / Histopathologische Diagnostik von soliden und zystischen Pankreasläsionen mit Hauptaugenmerk auf dem duktalen Adenokarzinom : Ein Vademecum für den Alltag.

Pancreas pathology is constantly evolving and can present various challenges for pathologists. This paper is focused on providing helpful hints for daily routine diagnostics. During histopathological analysis of pancreas biopsies, pancreatic ductal adenocarcinoma must be distinguished not only from other solid neoplasms, but especially from its mimicker, autoimmune pancreatitis. This can be achieved by a systematic workup following clear diagnostic criteria. When analyzing samples from cystic pancreatic lesions, mucin-producing neoplasms must be detected due to their role as pancreatic cancer precursors; molecular analyses can help considerably with their detection and distinction. During frozen section examination, evaluation of the pancreatic neck margin and analysis of unclear lesions of the liver are two important tasks, which are explained further in this article. A special challenge is the evaluation of neoadjuvant treated pancreatic cancer, which requires a detailed macroscopic and microscopic workup. Finally, current advances in precision oncology and emerging approaches for pancreatic cancer within this field are discussed. With the advancement of technical possibilities and their increasingly broad implementation, the classification systems in pancreatic pathology will continue to gain in complexity, but also in accuracy.

Revisiting the performance of cyst fluid carcinoembryonic antigen as a diagnostic marker for pancreatic mucinous cysts: a comprehensive 20-year institutional review.

OBJECTIVE: Elevated pancreatic cyst fluid carcinoembryonic antigen (CEA) has been routinely used to classify mucinous cysts. This study incorporates original data that established the CEA ≥192 ng/mL threshold with over 20 years of additional data and reassesses the diagnostic performance of CEA for differentiating mucinous from non-mucinous cysts. DESIGN: 1169 pancreatic cysts (1999-2021) with CEA results were identified. 394 cases had histological confirmation as the diagnostic standard. Additionally, 237 cysts without histological confirmation demonstrated KRAS, GNAS, or RNF43 mutations by molecular testing and were combined with the histologically confirmed cysts for separate analysis on a total cohort of 631 cysts. RESULTS: Median CEA was significantly higher in mucinous cysts (323.9 ng/mL, n=314) versus non-mucinous cysts (204.6 ng/mL, n=80) (p<0.001). Receiver operating characteristic curve analysis demonstrated an optimal CEA cut-off of 20 ng/mL (area under the curve: 80%), though the specificity was lower than desired (sensitivity 89%, specificity 64%). At the previously established threshold of 192 ng/mL, sensitivity and specificity were 56% and 78%, respectively. To achieve a specificity of 85% as originally reported, a CEA threshold of 250 ng/mL was needed; the 13 false positive cases at this threshold included 4 benign simple cysts, 2 squamoid cysts, 1 serous cystadenoma, 1 lymphoepithelial cyst and 5 more uncommon entities. All results remained similar within the total cohort after including additional cases with KRAS/GNAS/RNF43 mutations only. CONCLUSION: Cyst fluid CEA continues to be a useful test in the diagnosis of mucinous pancreatic cysts but does not appear as specific as previously reported. Raising the CEA threshold to 250 ng/mL to maintain specificity for differentiating mucinous from non-mucinous cysts may be considered.

Pancreatic cyst features predict future development of pancreatic cancer: results of a nested case-control study.

BACKGROUND AND AIMS: Risk factors for pancreatic cancer among patients with pancreatic cysts are incompletely characterized. The primary aim of this study was to evaluate risk factors for development of pancreatic cancer among patients with pancreatic cysts. METHODS: We conducted a retrospective case-control study of U.S. veterans with a suspected diagnosis of branch-duct intraductal papillary mucinous neoplasm from 1999 to 2013. RESULTS: Age (hazard ratio [HR], 1.03 per year; 95% confidence interval [CI], 1.00-1.06), larger cyst size at cyst diagnosis (HR, 1.03 per mm; 95% CI, 1.01-1.04), cyst growth rate (HR, 1.22 per mm/y; 95% CI, 1.14-1.31), and pancreatic duct dilation (5-9.9 mm: HR, 3.78; 95% CI, 1.90-7.51; ≥10 mm: HR, 13.57; 95% CI, 5.49-33.53) were found to be significant predictors for pancreatic cancer on multivariable analysis. CONCLUSIONS: Age, cyst size, cyst growth rate, and high-risk or worrisome features were associated with a higher risk of developing pancreatic cancer. Applying current and developing novel strategies is required to optimize early detection of pancreatic cancer after cyst diagnosis.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: The present study suggests that the incidence of IPMN increases with age and is accelerated in the presence of MS.

Tracking incidentally discovered pancreatic cysts smaller than 30 mm: Natural course and predictors of malignancy.

BACKGROUND AND AIMS: The aim of this study was to assess the natural course and predictors of malignancy in incidentally detected small pancreatic cysts (PCs). METHOD: We retrospectively included patients with PCs smaller than 30 mm followed up with the same cross-sectional imaging modality at least 12 months apart between January 2010 and December 2019 in three academic institutions. Cyst growth, pancreatic cancer incidence, and associated factors associated with pancreatic cancer were analyzed. RESULTS: A total of 1109 patients were followed up for a median of 34 months (range, 12‒118 months). Cyst growth and rapid cyst growth (≥ 5 mm/2 years) during follow-up were observed in 20.7% and 8.3%, respectively, both with higher rates for 15‒30 mm sized PCs. Eight patients were diagnosed with pancreatic cancer. The standardized incidence ratio for pancreatic cancer in small PCs was calculated as 5.2 [95% Confidence interval (CI): 1.3‒20.5].  The development of pancreatic cancer was associated with rapid growth [hazard ratio (HR): 8.1, 95% CI: 1.5‒43.4, p = 0.015] and newly developed worrisome features (HR: 11.7, 95% CI: 1.7‒79.6, p = 0.012) in competing risk analysis. CONCLUSIONS: One-fifth of small incidentally detected PCs increased in size. Rapid growth and newly developed worrisome features were predictors of malignancy.

[Challenges of cytopathological pancreas diagnostics]. / Herausforderungen der zytopathologischen Pankreasdiagnostik.

The cytologic diagnostics of solid and cystic pancreatic lesions with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is an integral part of the clinical workup and the decision of a surgical versus a conservative approach. Cystic lesions are increasingly being diagnosed due to improved imaging and represent numerous neoplastic as well as non-neoplastic epithelial and non-epithelial entities, which differ in biological behavior and prognosis. In particular, the differentiation of mucinous and non-mucinous cysts is significant for further clinical management. Regressive cellular changes, gastrointestinal contaminants, and overlapping morphologic changes of reactively altered ductal epithelial cells and cells of well-differentiated neoplasms and preneoplasms are special challenges of cytological diagnostics. For a uniform cytological classification of findings, an internationally developed seven-level classification system has been published and co-published by the World Health Organization (WHO). This classification system takes into account both morphological findings and further procedures on cytological material such as next-generation sequencing and immunocytochemistry and is based on the WHO classification for pancreatic tumors. Against this background, important cytologic diagnostic criteria of various solid and cystic lesions relevant in clinical practice are presented in this article, considering diagnostic possibilities and pitfalls as well as differential diagnoses.

MC3DU-Net: a multisequence cascaded pipeline for the detection and segmentation of pancreatic cysts in MRI.

PURPOSE: Radiological detection and follow-up of pancreatic cysts in multisequence MRI studies are required to assess the likelihood of their malignancy and to determine their treatment. The evaluation requires expertise and has not been automated. This paper presents MC3DU-Net, a novel multisequence cascaded pipeline for the detection and segmentation of pancreatic cysts in MRI studies consisting of coronal MRCP and axial TSE MRI sequences. METHODS: MC3DU-Net leverages the information in both sequences by computing a pancreas Region of Interest (ROI) segmentation in the TSE MRI scan, transferring it to MRCP scan, and then detecting and segmenting the cysts in the ROI of the MRCP scan. Both the voxel-level ROI of the pancreas and the segmentation of the cysts are performed with 3D U-Nets trained with Hard Negative Patch Mining, a new technique for class imbalance correction and for the reduction in false positives. RESULTS: MC3DU-Net was evaluated on a dataset of 158 MRI patient studies with a training/validation/testing split of 118/17/23. Ground truth segmentations of a total of 840 cysts were manually obtained by expert clinicians. MC3DU-Net achieves a mean recall of 0.80 ± 0.19, a mean precision of 0.75 ± 0.26, a mean Dice score of 0.80 ± 0.19 and a mean ASSD of 0.60 ± 0.53 for pancreatic cysts of diameter > 5 mm, which is the clinically relevant endpoint. CONCLUSION: MC3DU-Net is the first fully automatic method for detection and segmentation of pancreatic cysts in MRI. Automatic detection and segmentation of pancreatic cysts in MRI can be performed accurately and reliably. It may provide a method for precise disease evaluation and may serve as a second expert reader.

Fine-needle aspiration of a pancreas with squamoid cyst of pancreatic duct and pancreatic duct stones: A case report of a rare pancreatic lesion and an unusual concurrent finding of stone-related crystals.

Squamoid cyst of pancreatic duct is a rare benign pancreatic lesion that is rarely encountered in fine-needle aspiration (FNA) and surgical resection specimens. Pancreatic stones can be seen in chronic pancreatitis, but stone-related crystals have previously not been described in pancreatic cytology. Presented here is a case report of a squamoid cyst of pancreatic duct with concurrent pancreatic duct stones. We describe the cytomorphology of this benign cyst, as well as the remarkable finding of polymorphous crystals on cyst fluid aspirate. We also describe the histology of the surgically resected cystic lesion. With the increase in detection of incidental pancreatic cysts on imaging, this case highlights the importance of awareness and recognition of benign non-neoplastic epithelial cysts on FNA sampling to avoid overtreatment. The presence of crystals on pancreatic FNA is an unusual finding, likely representing calcium carbonate crystals related to the formation of pancreatic duct stones.

Risk Factors for Progression in Patients Undergoing Surveillance for Pancreatic Cysts.

OBJECTIVE: To identify risk factors associated with the progression of pancreatic cysts in patients undergoing surveillance. BACKGROUND: Previous studies of intraductal papillary mucinous neoplasms (IPMNs) rely on surgical series to determine malignancy risk and have inconsistently identified characteristics associated with IPMN progression. METHODS: We conducted a retrospective review of 2197 patients presenting with imaging concerning for IPMN from 2010 to 2019 at a single institution. Cyst progression was defined as resection or pancreatic cancer development. RESULTS: The median follow-up time was 84 months from the presentation. The median age was 66 years, and 62% were female. Ten percent had a first-degree relative with pancreatic cancer, and 3.2% had a germline mutation or genetic syndrome associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). Cumulative incidence of progression was 17.8% and 20.0% at 12 and 60 months postpresentation, respectively. Surgical pathology for 417 resected cases showed noninvasive IPMN in 39% of cases and PDAC with or without associated IPMN in 20%. Only 18 patients developed PDAC after 6 months of surveillance (0.8%). On multivariable analysis, symptomatic disease [hazard ratio (HR)=1.58; 95% CI: 1.25-2.01], current smoker status (HR=1.58; 95% CI: 1.16-2.15), cyst size (HR=1.26; 95% CI: 1.20-1.33), main duct dilation (HR=3.17; 95% CI: 2.44-4.11), and solid components (HR=1.89; 95% CI: 1.34-2.66) were associated with progression. CONCLUSIONS: Worrisome features on imaging at presentation, current smoker status, and symptomatic presentation are associated with IPMN progression. Most patients progressed within the first year of presentation to Memorial Sloan Kettering Cancer Center (MSKCC). Further investigation is necessary to develop personalized cyst surveillance strategies.

The Deception of Pancreas Cyst Surveillance: A Case Study.

Pancreatic cysts are a growing pandemic around the world. Intrapapillary mucinous neoplasms are the most common type of pancreatic cysts and given their premalignant nature, guidelines recommend surveillance. This case study and discussion addresses the five existing guidelines published to help clinicians manage patients with intraductal papillary mucinous neoplasms and illustrates how, despite guidelines and close surveillance, intraductal papillary mucinous neoplasms can transform into pancreatic adenocarcinoma.