Cyst fluid glucose: An alternative to carcinoembryonic antigen for pancreatic mucinous cysts

Pancreatic cystic lesions(PCLs) have been increasingly recognized in clinical practice. Although inflammatory cysts(pseudocysts) are the most common PCLs detected by cross-sectional imaging modalities in symptomatic patients in a setting of acute or chronic pancreatitis, incidental pancreatic cysts with no symptoms or history of pancreatitis are usually neoplastic cysts. For these lesions,it is imperative to identify mucinous cysts(intraductal papillary mucinous neoplasms and mucinous cystic neoplasms) due to the risk of their progression to malignancy. However, no single imaging modality alone is sufficient for a definitive diagnosis of all PCLs. The cyst fluid obtained by endoscopic ultrasound-guided fine needle aspiration provides additional information for the differential diagnosis of PCLs. Current recommendations suggest sending cyst fluid for cytology evaluation and measurement of carcinoembryonic antigen(CEA) levels. Unfortunately, the sensitivity of cytology is greatly limited, and cyst fluid CEA has demonstrated insufficient accuracy as a predictor of mucinous cysts. More recently, cyst fluid glucose has emerged as an alternative to CEA for distinguishing between mucinous and nonmucinous lesions. Herein, the clinical utility of cyst fluid glucose and CEA for the differential diagnosis of PCLs was evaluated.     

Updates in diagnosis and management of pancreatic cysts

Incidental pancreatic cysts are commonly encountered with some cysts having malignant potential. The most common pancreatic cystic neoplasms include serous cystadenoma, mucinous cystic neoplasm and intraductal papillary mucinous neoplasm. Risk stratifying pancreatic cysts is important in deciding whether patients may benefit from endoscopic ultrasound (EUS) or surgical resection. Surgery should be reserved for patients with malignant cysts or cysts at high risk for developing malignancy as suggested by various risk features including solid mass, nodule and dilated main pancreatic duct. EUS may supplement magnetic resonance imaging findings for cysts that remain indeterminate or have concerning features on imaging. Various cyst fluid markers including carcinoembryonic antigen, glucose, amylase, cytology, and DNA markers help distinguish mucinous from nonmucinous cysts. This review will guide the practicing gastroenterologist in how to evaluate incidental pancreatic cysts and when to consider referral for EUS or surgery. For presumed low risk cysts, surveillance strategies will be discussed. Managing pancreatic cysts requires an individualized approach that is directed by the various guidelines.     

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic cysts by combined cytopathology and cystic content analysis

Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUS-guided FNA and the cytological diagnosis for pancreatic cysts.     

Molecular analysis of pancreatic cystic neoplasm in routine clinical practice

BACKGROUNDCystic pancreatic lesions consist of a wide variety of lesions that are becoming increasingly diagnosed with the growing use of imaging techniques. Of these, mucinous cysts are especially relevant due to their risk of malignancy. However, morphological findings are often suboptimal for their differentiation. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) with molecular analysis has been suggested to improve the diagnosis of pancreatic cysts.AIMTo determine the impact of molecular analysis on the detection of mucinous cysts and malignancy.METHODSAn 18-month prospective observational study of consecutive patients with pancreatic cystic lesions and an indication for EUS-FNA following European clinical practice guidelines was conducted. These cysts included those > 15 mm with unclear diagnosis, and a change in follow-up or with concerning features in which results might change clinical management. EUS-FNA with cytological, biochemical and glucose and molecular analyses with next-generation sequencing were performed in 36 pancreatic cysts. The cysts were classified as mucinous and non-mucinous by the combination of morphological, cytological and biochemical analyses when surgery was not performed. Malignancy was defined as cytology positive for malignancy, high-grade dysplasia or invasive carcinoma on surgical specimen, clinical or morphological progression, metastasis or death related to neoplastic complications during the 6-mo follow-up period. Next-generation sequencing results were compared for cyst type and malignancy.RESULTSOf the 36 lesions included, 28 (82.4%) were classified as mucinous and 6 (17.6%) as non-mucinous. Furthermore, 5 (13.9%) lesions were classified as malignant. The amount of deoxyribonucleic acid obtained was sufficient for molecular analysis in 25 (69.4%) pancreatic cysts. The amount of intracystic deoxyribonucleic acid was not statistically related to the cyst fluid volume obtained from the lesions. Analysis of KRAS and/or GNAS showed 83.33% [95% confidence interval (CI): 63.34-100] sensitivity, 60% (95%CI: 7.06-100) specificity, 88.24% (95%CI: 69.98-100) positive predictive value and 50% (95%CI: 1.66-98.34) negative predictive value (P = 0.086) for the diagnosis of mucinous cystic lesions. Mutations in KRAS and GNAS were found in 2/5 (40%) of the lesions classified as non-mucinous, thus recategorizing those lesions as mucinous neoplasms, which would have led to a modification of the follow-up plan in 8% of the cysts in which molecular analysis was successfully performed. All 4 (100%) malignant cysts in which molecular analysis could be performed had mutations in KRAS and/or GNAS, although they were not related to malignancy (P > 0.05). None of the other mutations analyzed could detect mucinous or malignant cysts with statistical significance (P > 0.05). CONCLUSIONMolecular analysis can improve the classification of pancreatic cysts as mucinous or non-mucinous. Mutations were not able to detect malignant lesions.     

Combination of cyst fluid CEA and CA 125 is an accurate diagnostic tool for differentiating mucinous cystic neoplasms from intraductal papillary mucinous neoplasms

Background/objectivesDespite advances in imaging techniques, diagnosis and management of pancreatic cystic lesions still remains challenging. The objective of this study was to determine the utility of cyst fluid analysis (CEA, CA 19-9, CA 125, amylase, and cytology) in categorizing pancreatic cystic lesions, and in differentiating malignant from benign cystic lesions.MethodsA retrospective analysis of 68 patients with histologically and clinically confirmed cystic lesions was performed. Cyst fluid was obtained by surgical resection (n = 45) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) (n = 23). Cyst fluid tumor markers and amylase were measured and compared between the cyst types.ResultsReceiver operating characteristic (ROC) curve analysis of the tumor markers demonstrated that cyst fluid CEA provided the greatest area under ROC curve (AUC) (0.884) for differentiating mucinous versus non-mucinous cystic lesions. When a CEA cutoff value was set at 67.3 ng/ml, the sensitivity, specificity and accuracy for diagnosing mucinous cysts were 89.2%, 77.8%, and 84.4%, respectively. The combination of cyst fluid CEA content >67.3 ng/ml and cyst fluid CA 125 content >10.0 U/ml segregated 77.8% (14/18) of mucinous cystic neoplasms (MCNs) from other cyst subtypes. On the other hand, no fluid marker was useful for differentiating malignant versus benign cystic lesions. Although cytology (accuracy 83.3%) more accurately diagnosed malignant cysts than CEA (accuracy 65.6%), it lacked sensitivity (35.3%).ConclusionsOur results demonstrate that cyst fluid CEA can be a helpful marker in differentiating mucinous from non-mucinous, but not malignant from benign cystic lesions. A combined CEA and CA 125 approach may help segregate MCNs from IPMNs.     

Appraisal of needle-based confocal laser endomicroscopy in the diagnosis of pancreatic cysts

Nearly 2.5% of cross-sectional imaging studies will report a finding of a cystic pancreatic lesion. Eventhough most of these are incidental findings, it remains very concerning for both patients and treating clinicians. Differentiating and predicting malignant transformation in pancreatic cystic lesions is clinically challenging. Current evaluation of suspicious cystic lesions includes a combination of radiologic imaging, endoscopic ultrasound(EUS) and cyst fluid analyses. Despite these attempts, precise diagnostic stratification among nonmucinous, mucinous, and malignant cystic lesions is often not possible until surgical resection. EUS-guided needle based confocal laser endomicroscopy(n CLE) for evaluation of pancreatic cysts is emerging as a powerful technique with remarkable potential. Though limited imaging data from 3 large clinical trials(INSPECT, DETECT and CONTACT) are currently the reference standard for n CLE imaging, nonetheless these have not been validated in large studies. The aim of this review article is to review the evolving role of EUS-guided n CLE in management of pancreatic cystic lesions in terms of its significance, adverse events, limitations, and implications.     

Recent advances in the diagnostic evaluation of pancreatic cystic lesions

Pancreatic cystic lesions (PCLs) are becoming more prevalent due to more frequent abdominal imaging and the increasing age of the general population. It has become crucial to identify these PCLs and subsequently risk stratify them to guide management. Given the high morbidity associated with pancreatic surgery, only those PCLs at high risk for malignancy should undergo such treatment. However, current diagnostic testing is suboptimal at accurately diagnosing and risk stratifying PCLs. Therefore, research has focused on developing new techniques for differentiating mucinous from non-mucinous PCLs and identifying high risk lesions for malignancy. Cross sectional imaging radiomics can potentially improve the predictive accuracy of primary risk stratification of PCLs at the time of detection to guide invasive testing. While cyst fluid glucose has reemerged as a potential biomarker, cyst fluid molecular markers have improved accuracy for identifying specific types of PCLs. Endoscopic ultrasound guided approaches such as confocal laser endomicroscopy and through the needle microforceps biopsy have shown a good correlation with histopathological findings and are evolving techniques for identifying and risk stratifying PCLs. While most of these recent diagnostics are only practiced at selective tertiary care centers, they hold a promise that management of PCLs will only get better in the future.     

Surgical Management of Pancreatic Cysts: A Shifting Paradigm Toward Selective Resection

Due to the widespread use of high-quality cross-sectional imaging, pancreatic cystic neoplasms are being diagnosed with increasing frequency. Clinicians are therefore asked to counsel a growing number of patients with pancreatic cysts diagnosed incidentally at an early, asymptomatic stage. Over the last two decades, accumulating knowledge on the biologic behavior of these neoplasms along with improved diagnostics through imaging and endoscopic cyst fluid analysis have allowed for a selective therapeutic approach toward these neoplasms. On one end of the management spectrum, observation is recommended for typically benign lesions (serous cystadenoma), and on the other end, upfront resection is recommended for likely malignant lesions (main duct IPMN, mucinous cystadenoma, solid pseudopapillary tumor, and cystic pancreatic neuroendocrine tumors). In between, management of premalignant lesions (branch duct IPMN) is dictated by the presence of high-risk features. In general, resection should be considered whenever the risk of malignancy is higher than the risk of the operation. This review aims to describe the evolution and current status of evidence guiding the selection of patients with pancreatic cystic neoplasms for surgical resection, along with a specific discussion on the type of resection required and expected outcomes.     

Long-term follow-up of neoplastic pancreatic cysts without high-risk stigmata: how often do we change treatment strategy because of malignant transformation?

*Objective: Patients with potentially premalignant neoplastic pancreatic cysts without high-risk stigmata usually enter a surveillance program. Data on outcomes of such surveillance programs are scarce. We aimed to evaluate the resection rate and malignancy rate during follow-up.

Material and methods: From our prospective database (2006–2015) of patients with pancreatic cysts, we analyzed patients with pancreatic cysts without high-risk stigmata with at least six months follow-up.

Results: In total, 146 patients were followed for a median of 29 months (IQR 13.5–50 months). In 124 patients (84.9%), no changes in clinical or imaging characteristics occurred during follow-up. Thirteen patients (8.9%) developed an indication for surgery after a median follow-up of 25 months (IQR 12–42 months). Two patients did not undergo surgery because of comorbidity, 11 patients (7.5%) underwent resection. Indications for surgery were symptoms (n?=?2), development of a pancreatic mass (n?=?1), a new nodule (n?=?2), thickened cyst wall (n?=?1), pancreatic duct dilation (n?=?3), and/or suspicion of mucinous cystic neoplasm (MCN) (n?=?3). Postoperative histology showed one pancreatic malignancy not originating from the cyst, three mixed type-intraductal papillary mucinous neoplasm (IPMN), one side branch-IPMN, two MCN, one neuroendocrine tumor, one serous cystadenoma, one inflammatory cyst, and one lymphangioma. The highest grade of cyst dysplasia was borderline dysplasia.

Conclusions: Most neoplastic pancreatic cysts without high-risk stigmata at initial presentation show no substantial change during 1–4-year follow-up. Only 7.5% of patients underwent surgery and less than 1% of patients developed pancreatic malignancy. This indicates that additional markers are needed to tailor treatment of pancreatic cysts.     

Beobachtung zystischer Pankreastumoren

At least 1 out of 40 adults without pre-existing pancreatic disease has a pancreatic cyst. Hence prophylactic resection of every cystic lesion is not a viable approach. However, in the total group of pancreatic cysts, mucinous cystic neoplasms are found in women aged 40–60 years and intraductal papillary mucinous neoplasms (IPNM) are more frequent in the group over 60 years old. Both entities bear a relevant potential of malignancy requiring a careful work-up including case history and qualified examinations with endoscopic ultrasound or magnetic resonance imaging. Using the diagnostic algorithm presented here the risk for an individual patient can be assessed. A resection of the cyst is recommended in cases of main duct IPNM, obstructive jaundice, cysts with solid parts and a lesion size of more than 3 cm. Even below this size increased attention is warranted in certain cases. For the majority of patients only one or a few control examinations are sufficient. After partial resection of the pancreas follow-up studies are necessary in cases of IPNM due to the risk of recurrence.     

Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions

Abstract Background. Magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are considered useful techniques in the evaluation of pancreatic cysts. Aim of this study was to prospectively compare the diagnostic value of these techniques. Methods. This study included consecutive patients who underwent MRI, EUS, and EUS-FNA for a pancreatic cyst that was eventually resected surgically. Observers scored for cyst characteristics, a distinction between mucinous and non-mucinous cysts and a suspicion of malignancy. The interobserver agreement between MRI and EUS was calculated. Results. A total of 32 patients were included. Sensitivity for diagnosing a mucinous cyst was 78% for EUS versus 91% for MRI. Sensitivity for detecting malignancy was 25% (1/4) and 50% (2/4) for EUS and MRI respectively. Sensitivity of EUS-FNA for diagnosing a mucinous cyst (positive cytology and/or CEA >192 ng/ml) was 61%. Sensitivity for detecting malignancy (positive cytology) was 1/4 (25%). Interobserver agreement between MRI and EUS for the features was poor to fair. Conclusion. MRI and EUS are comparable techniques for the morphological characterization of pancreatic cysts. Combined sensitivity of EUS and MRI was higher than the sensitivity of one of the techniques alone. For diagnosing a mucinous cyst, FNA findings showed a low sensitivity, but a high specificity.     

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.     

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.     

Pancreatic Cystic Lesions: When to Watch,When to Operate,and When to Ignore

Pancreatic cystic lesions are being increasingly identified with the widespread use of state-of-the-art imaging. These lesions are categorized into a broad range of neoplastic cysts and inflammatory pseudocysts. Identification of a pancreatic cyst requires the clinician to focus on the main clinical challenge of the benign or malignant nature of the cyst. Neoplastic cysts range the spectrum from benign, to premalignant, to frank malignancy. The management of these lesions is difficult, and the decision to resect or observe a lesion is hampered by limitations in current imaging and tissue sampling techniques that prevent the accurate characterization of all lesions. This article reviews current guidelines for the evaluation of pancreatic cystic lesions, underscores the challenges posed by these lesions, and discusses current and future studies that will aid in patient management.     

Concomitant pancreatic adenocarcinoma in a patient with branch-duct intraductal papillary mucinous neoplasm

Branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are pre-malignant pancreatic cystic lesions which carry a small risk of malignant transformation within the cyst. Guidelines exist with respect to surveillance of the cysts using computed tomography, magnetic resonance imaging, and/or endoscopic ultrasound (EUS). There are reports that patients with IPMNs are at increased risk of developing pancreatic adenocarcinoma, which arises in an area separate to the IPMNs. We present two cases of pancreatic adenocarcinoma arising within the parenchyma, distinct from the IPMN-associated cyst, identified with EUS. This case report highlights that patients with BD-IPMN are at increased risk for pancreatic adenocarcinoma separate from the cyst and also the importance for endosonographers to carefully survey the rest of the pancreatic parenchyma separate from the cyst in order to identify small pancreatic adenocarcinomas.     

Management of mucinous cystic neoplasms of the pancreas

The purpose of this study was to investigate the actual management of mucinous cystic neoplasm (MCN) of the pancreas. A systematic review was performed in December 2009 by consulting PubMed MEDLINE for publications and matching the "pancreatic mucinous cystic neoplasm", "pancreatic mucinous cystic tumour", "pancreatic mucinous cystic mass", "pancreatic cyst", and "pancreatic cystic neoplasm" to identify English language articles describing the diagnosis and treatment of the mucinous cystic neoplasm of the pancreas. In total, 16 322 references ranging from January 1969 to December 2009 were analysed and 77 articles were identified. No articles published before 1996 were selected because MCNs were not previously considered to be a completely autonomous disease. Definition, epidemiology, anatomopathological findings, clinical presentation, preoperative evaluation, treatment and prognosis were reviewed. MCNs are pancreatic mucinproducing cysts with a distinctive ovarian-type stroma localized in the body-tail of the gland and occurring in middle-aged females. The majority of MCNs are slow growing and asymptomatic. The prevalence of invasive carcinoma varies between 6% and 55%. Preoperative diagnosis depends on a combination of clinical features, tumor markers, computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound with cyst fluid analysis, and positron emission tomography-CT. Surgery is indicated for all MCNs.     

Cytopathological Analysis of Cyst Fluid Enhances Diagnostic Accuracy of Mucinous Pancreatic Cystic Neoplasms

Widespread use of cross-sectional imaging and increasing age of the general population has increased the number of detected pancreatic cystic lesions. However, several pathological entities with a variety in malignant potential have to be discriminated to allow clinical decision making. Discrimination between mucinous pancreatic cystic neoplasms (PCNs) and nonmucinous pancreatic lesions is the primary step in the clinical work-up, as malignant transformation is mostly associated with mucinous PCN. We performed a retrospective analysis of all resected PCN in our tertiary center from 2000 to 2014, to evaluate preoperative diagnostic performance and the results of implementation of the consensus guidelines over time. This was followed by a prospective cohort study of patients with an undefined pancreatic cyst, where the added value of cytopathological mucin evaluation to carcinoembryonic antigen (CEA) in cyst fluid for the discrimination of mucinous PCN and nonmucinous cysts was investigated. Retrospective analysis showed 115 patients operated for a PCN, with a correct preoperative classification in 96.2% of the patients. High-grade dysplasia or invasive carcinoma was observed in only 32.3% of mucinous PCN. In our prospective cohort (n = 71), 57.7% of patients were classified as having a mucinous PCN. CEA ≥192 ng/mL had an accuracy of 63.4%, and cytopathological mucin evaluation an accuracy of 73.0%. Combining these 2 tests further improved diagnostic accuracy of a mucinous PCN to 76.8%. CEA level and mucin evaluation were not predictive of the degree of dysplasia. These findings show that adding cytopathology to cyst fluid biochemistry improves discrimination between mucinous PCN and nonmucinous cysts.     

European experts consensus statement on cystic tumours of the pancreas

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6 mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.     

Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions

Abstract

Background. Magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are considered useful techniques in the evaluation of pancreatic cysts. Aim of this study was to prospectively compare the diagnostic value of these techniques. Methods. This study included consecutive patients who underwent MRI, EUS, and EUS-FNA for a pancreatic cyst that was eventually resected surgically. Observers scored for cyst characteristics, a distinction between mucinous and non-mucinous cysts and a suspicion of malignancy. The interobserver agreement between MRI and EUS was calculated. Results. A total of 32 patients were included. Sensitivity for diagnosing a mucinous cyst was 78% for EUS versus 91% for MRI. Sensitivity for detecting malignancy was 25% (1/4) and 50% (2/4) for EUS and MRI respectively. Sensitivity of EUS-FNA for diagnosing a mucinous cyst (positive cytology and/or CEA >192 ng/ml) was 61%. Sensitivity for detecting malignancy (positive cytology) was 1/4 (25%). Interobserver agreement between MRI and EUS for the features was poor to fair. Conclusion. MRI and EUS are comparable techniques for the morphological characterization of pancreatic cysts. Combined sensitivity of EUS and MRI was higher than the sensitivity of one of the techniques alone. For diagnosing a mucinous cyst, FNA findings showed a low sensitivity, but a high specificity.