Management of Pancreatic Cystic Lesions.

BACKGROUND: The prevalence of undefined pancreatic cystic neoplasms (PCNs) is high in the general population, increasing with patient age. PCNs account for different biological entities with different potential for malignant transformation. The clinician must balance his or her practice between the risk of surgical overtreatment and the error of keeping a malignant lesion under surveillance. METHODS: We review and discuss the clinical management of PCNs. Specifically, we analyze the main features of PCNs from the surgeon's point of view, as they present in the outpatient clinic. We also review the different consensus guidelines, address recent controversies in the literature, and present the current clinical practice at 4 different European Centers for pancreatic surgery. RESULTS: The main features of PCNs were analyzed from the surgeon's point of view as they present in the outpatient clinic. All aspects of surgical management were discussed, from indications for surgery to intraoperative management and surveillance strategies. CONCLUSIONS: Management of PCNs requires a selective approach with the aim of minimizing clinically relevant diagnostic mistakes. Through the evaluation of clinical and radiological features of a PCN, the surgeon can elaborate on a diagnostic hypothesis and assess malignancy risk, but the final decision should be tailored to the individual patient's need.

Integrated targeted metabolomic and lipidomic analysis: A novel approach to classifying early cystic precursors to invasive pancreatic cancer.

Pancreatic cystic neoplasms (PCNs) are a highly prevalent disease of the pancreas. Among PCNs, Intraductal Papillary Mucinous Neoplasms (IPMNs) are common lesions that may progress from low-grade dysplasia (LGD) through high-grade dysplasia (HGD) to invasive cancer. Accurate discrimination of IPMN-associated neoplastic grade is an unmet clinical need. Targeted (semi)quantitative analysis of 100 metabolites and >1000 lipid species were performed on peri-operative pancreatic cyst fluid and pre-operative plasma from IPMN and serous cystic neoplasm (SCN) patients in a pancreas resection cohort (n = 35). Profiles were correlated against histological diagnosis and clinical parameters after correction for confounding factors. Integrated data modeling was used for group classification and selection of the best explanatory molecules. Over 1000 different compounds were identified in plasma and cyst fluid. IPMN profiles showed significant lipid pathway alterations compared to SCN. Integrated data modeling discriminated between IPMN and SCN with 100% accuracy and distinguished IPMN LGD or IPMN HGD and invasive cancer with up to 90.06% accuracy. Free fatty acids, ceramides, and triacylglycerol classes in plasma correlated with circulating levels of CA19-9, albumin and bilirubin. Integrated metabolomic and lipidomic analysis of plasma or cyst fluid can improve discrimination of IPMN from SCN and within PMNs predict the grade of dysplasia.

Simple Mucinous Cyst of the Pancreas: Review and Update.

CONTEXT: - According to the 2014 Baltimore Consensus Meeting, simple mucinous cysts are defined as macroscopic cysts that are greater than 1 cm in size with gastric-type flat mucinous lining and minimal cytologic atypia without ovarian-type stroma. This lesion has not been widely recognized and has undergone a recent nomenclature change owing to unclear pathogenesis and biologic behavior. Mucinous pancreatic cystic lesions are generally considered precursor lesions of pancreatic adenocarcinoma. However, simple mucinous cysts generally have benign behavior with no recurrence or malignant transformation during short follow-up periods. OBJECTIVE: - To provide a brief update and summary of the evolving nomenclature and current knowledge of simple mucinous cysts with an overview of their clinical, histopathologic, immunohistochemical, and molecular characteristics, as well as discussion of their differential diagnoses and biological behavior. DATA SOURCES: - Analysis of the pertinent literature (PubMed) and authors' clinical practice experience based on institutional and consultation materials. CONCLUSIONS: - Simple mucinous cyst has undergone a nomenclature evolution from mucinous nonneoplastic cyst to the current recommended name of simple mucinous cyst to reflect its unclear pathogenesis and progression. The malignant potential of simple mucinous cyst is still debatable. Recent molecular studies support a neoplastic process, but these cysts generally exhibit benign behavior without recurrence or malignant transformation. Therefore, accurate diagnosis of simple mucinous cysts is critical to distinguish them from other more common and aggressive mucinous pancreatic cysts. Studies with larger cohorts and longer clinical follow-up data are needed to further determine the biologic behavior of this cyst and implications for prognosis.

My Treatment Approach: Pancreatic Cysts.

Our treatment approach for either symptomatic or incidentally found pancreatic cysts continues to improve. The true incidence of pancreatic cysts is not known, and pancreatic cystic neoplasms, especially intraductal papillary mucinous neoplasms, are currently most commonly diagnosed and resected. This is a result of increasing awareness, widespread availability of imaging, and better understanding of the nature of pancreatic cysts as well. Recent studies on molecular analysis and devices such as microbiopsy forceps help us better define and select the treatment approach to alleviate symptoms and to prevent malignant tumors while avoiding unnecessary surgery.

The role of surgery in cystic lesions of the pancreas.

The incidence of cystic neoplasms of the pancreas (CNP) is steadily increasing, most likely due to the commonly increased use of cross-sectional abdominal imaging. Most of these lesions are benign at the time of initial presentation, but some harbor malignant potential that either requires constant surveillance or surgical resection. However, it is still unclear when resection is mandated and when observation is sufficient. Moreover, the extent of resection and the technique used are also a matter of debate since limited resection and minimally invasive procedures are becoming more popular. Therefore, the aim of this review was to assess the role of surgery for the management of CNPs with an emphasis on novel procedures.

Pancreatic Cystic Lesions: Diagnostic, Management and Indications for Operation. Part I.

We notice an increasing frequency in the detection and evaluation of pancreatic cystic lesions (PCLs) over the last three decades. They show awide spectrum of imaging and clinical features. The diagnosis and discrimination of these lesions are very important because of the risk for concurrent or later development of malignancy. The main reason is the increased awareness of these lesions and the extensive use of cross-sectional imaging, an always improving technique (1). Commonly, PCLs are diagnosed incidentally during investigation for often unrelated and nonspecific abdominal complaints using state-of-the art abdominal imaging (CT, MRT). The term PCN denotes a histologically heterogeneous collection of neoplasms showing a wide spectrum of diagnoses, ranging from completely benign to potentially malignant, to carcinoma in situ, to frankly invasive and malignant (2,3). In 1978, Compagno and Oertel were the first to recognize the crucial distinction between the serous and the mucinous cystic neoplasms of the pancreas by explaining the importance of identifying the mucinous neoplasms because of their overt or latent malignant potential (4,5). Since then, the interest in PCLs increased markedly, especially so with the recognition of the importance and prevalence of intraductal papillary mucinous neoplasms (IPMNs). Nowadays, PCLs represent a common and often difficult challenge in clinical practice, because of the increase in their detection in asymptomatic patients and our still immature understanding of some aspects of their biologic behavior. Their important differences regarding their outcome and the fact of being increasingly often identified has put a special focus on these neoplasms by surgeons, pathologists, gastroenterologists, radiologists, and oncologists alike. Management of patients with PCNs can be challenging and varies considerably among the various subtypes of PCNs. Their treatment ranges from resection of malignant lesions, to resection and/or surveillance in the case of premalignant lesions, to simple observation in the case of benign or indolent lesions. Under these circumstances, the accurate classification of PCNs becomes crucial. Therapeutic decision making and classification rely mainly on the presenting symptoms and radiologic findings, often without actual histologic tissue. It is of extreme importance to identify suspicious features indicating potential or certain malignancy in order to select the appropriate treatment. The risk of overtreatment (unnecessary pancreatectomy) should he balanced carefully with the risk of under treatment (missing the opportunity to cure a potentially curable malignant or premalignant disease).

Impact of Pancreatic Cyst Fluid CEA Levels on the Classification of Pancreatic Cysts Using the Papanicolaou Society of Cytology Terminology System for Pancreaticobiliary Cytology.

BACKGROUND: The new proposed classification for pancreaticobiliary cytology has advocated the use of carcinoembryonic antigen (CEA) analysis of cyst fluid as an ancillary diagnostic tool for the determination of mucinous neoplasms in pancreatic cyst aspirates. We aimed to investigate the effect of CEA cyst fluid analysis on cases primarily called negative or nondiagnostic and on the sensitivity and specificity of the method. METHODS: We retrospectively identified and collected all pancreatic cyst aspirates from 2010 to 2014 at Mayo Clinic, Jacksonville, Florida, along with available corresponding surgical diagnoses. Cases primarily classified as nondiagnostic or negative but that had a cyst CEA level of 192 ng mL-1 or higher were reclassified as mucinous neoplasms. Cytohistologic correlation was assessed whenever possible. RESULTS: We retrieved pancreatic cyst aspirates from 255 patients who had a corresponding CEA level measurement. Median patient age was 70 years (range, 25-100 years). Among all samples, 129 (50.6%) had been classified as negative and 42 (16.4%) as nondiagnostic. Applying the new criteria, the number of samples previously classified as negative and nondiagnostic decreased considerably, with a statistically significant difference among negative cases. Fifty-four cases (21.2%) had an available corresponding surgical diagnosis, and complete agreement was achieved in 95.4% of the cases. Use of the new cutoff for CEA levels increased the sensitivity and negative predictive value, compared with the original diagnoses. CONCLUSIONS: The incorporation of the new proposed terminology and CEA fluid analysis has significantly decreased the number of samples primarily classified as negative and nondiagnostic, along with improved test characteristics. Diagn. Cytopathol. 2017;45:101-106. © 2016 Wiley Periodicals, Inc.

Spectrum and Classification of Cystic Neoplasms of the Pancreas.

As patients are living longer and axial imaging is more widespread, increasing numbers of cystic neoplasms of the pancreas are found. Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are the most common. The revised Sendai guidelines provide a safe algorithm for expectant management of certain cystic neoplasms; however, studies are ongoing to identify further subgroups that can be treated nonoperatively. For those patients with high-risk clinical features or symptoms, surgical resection can be performed safely at high-volume pancreatic centers. Accurate diagnosis is critical for accurate decision making.

A combination of molecular markers and clinical features improve the classification of pancreatic cysts.

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.

Premalignant cystic neoplasms of the pancreas.

Due to increasing utilization of cross-sectional imaging, asymptomatic pancreatic cysts are frequently being diagnosed. Many of these cysts have premalignant potential and offer a unique opportunity for cancer prevention. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are the major premalignant cystic neoplasms of pancreas. The prediction of the risk of malignancy (incidental and future risk of malignant transformation) and balancing the risks of watchful waiting with that of operative management with associated mortality and morbidity is the key to the management of these lesions. We review the literature that has contributed to the development of our approach to the management of these cystic neoplasms. We provide an overview of the key features used in diagnosis and in predicting malignancy. Particular attention is given to the natural history and management decision making.

[Classification and malignant potential of pancreatic cystic tumors]. / Klassifikation und malignes Potenzial der zystischen Pankreastumoren.

Cystic lesions of the pancreas are increasingly diagnosed with a reported prevalence of 10 % in 70-year-old individuals. Despite their broad spectrum, most resected cystic lesions can be attributed to one of the following entities: intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine cystic tumors (NECT), and solid pseudopapillary neoplasms (SPN). Among them, IPMN and MCN represent precursors of ductal adenocarcinoma, NECT and SPN are low-grade, potentially malignant lesions, and SCN are usually benign. Due to the not negligible morbidity and mortality rates in pancreatic surgery, even in highly specialized centers, an interdisciplinary preoperative stratification of pancreatic cystic lesions into high- and low-risk tumors is necessary in order to accurately select those cases that need to undergo immediate resection. The role of the pathologist is fundamental in both the preoperative assessment and in the postoperative classification, which determines prognosis, further treatment, and follow-up.

GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs".

Incipient intraductal papillary mucinous neoplasms (IPMNs) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs. They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs (≥ 1 cm). GNAS codon 201 mutations are hallmark genetic alterations of IPMNs. Hence, we sought to determine the GNAS status of incipient IPMNs to better classify these lesions. Incipient IPMNs from 3 institutions were histologically reassessed, manually microdissected, and the genomic DNA was extracted. Using a sensitive digital ligation technique, the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined. We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years (range, 40 to 76 y). Most patients underwent surgery for pancreatic ductal adenocarcinoma (N = 8) or ampullary adenocarcinoma (N = 3). The median incipient IPMN size was 4 mm (range, 2 to 7 mm), and a majority had gastric-foveolar (N = 11) or intestinal (N = 5) differentiation. The maximum dysplasia observed was intermediate, and most of the lesions had intermediate-grade dysplasia. Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs, whereas 7 lesions (33%) in 7 individual patients harbored GNAS codon 201 mutations. The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs. Morphologically, incipient IPMNs do not appear to be high-risk lesions. Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and, more importantly, to determine their clinical significance.

Acinar cell cystadenoma of the pancreas: a benign neoplasm or non-neoplastic ballooning of acinar and ductal epithelium?

Acinar cell cystadenoma (ACA) of the pancreas was initially described as a non-neoplastic cyst of the pancreas and, at that time, referred to as "acinar cystic transformation." In subsequent studies, these lesions were given the designation of "-oma," despite the relative lack of evidence supporting a neoplastic process. To characterize these lesions further, we examined the clinical, pathologic, and immunohistochemical features of 8 ACAs. The majority of patients were female (7 of 8, 88%) and ranged in age from 18 to 57 years (mean, 43 y). Grossly, the cysts involved the head (n=5), body (n=1), or the entire pancreas (n=2). ACAs were either multilocular (n=4) or unilocular (n=4) and ranged in size from 1.8 to 15 cm (mean, 6.8 cm). Histologically, multilocular ACAs were lined by patches of acinar and ductal epithelium. Immunolabeling, including double-labeling for cytokeratin 19 and chymotrypsin, highlighted the patchy pattern of the ductal and acinar cells lining the cysts. In some areas, the cysts with patches of acinar and ductal differentiation formed larger locules with incomplete septa as they appeared to fuse with other cysts. In contrast, the unilocular cases were lined by 1 to 2 cell layers of acinar cells with little intervening ductal epithelium. Nuclear atypia, mitotic figures, necrosis, infiltrative growth, and associated invasive carcinoma were absent in all cases. In addition, we assessed the clonal versus polyclonal nature of ACAs, occurring in women, using X-chromosome inactivation analysis of the human androgen receptor (AR) gene. Five of 7 cases were informative and demonstrated a random X-chromosome inactivation pattern. Clinical follow-up information was available for all patients, and follow-up ranged from 10 months to 7.8 years (mean, 3.6 y), with no evidence of recurrence or malignant transformation. We hypothesize that early lesions are marked by acinar dilatation that expands into and incorporates smaller ductules and later larger ducts. As the cysts increase in size, they fuse forming larger cysts. Later lesions demonstrate a unilocular cyst lined by predominantly acinar epithelium with scattered ductal cells. The term cystadenoma, with its neoplastic connotation, does not seem to accurately reflect the histologic, immunohistochemical, or molecular features of these lesions. We suggest readopting the term "acinar cystic transformation" until the non-neoplastic versus neoplastic origin of these lesions can be resolved.

To cease or 'de-cyst'? The evaluation and management of pancreatic cystic lesions.

Due to the widespread use of cross-sectional imaging and advances in imaging technology, pancreatic cystic lesions are increasingly being detected. The diagnosis and management of such cysts remains challenging and continues to evolve. Different pancreatic cyst types have varying malignant potential. Thus, accurate cyst characterization is essential to appropriate management; the most clinically important distinction is differentiating mucinous lesions, which have malignant potential and may benefit from surgical resection, from non-mucinous cystic lesions. Endoscopic ultrasound with fine needle aspiration with cytologic, chemical,, and tumor marker analysis appears to be the best currently available method for accurately characterizing a cyst's malignant potential, and therefore impacts the most important management decision for a pancreatic cyst-continued surveillance or surgical resection.

An efficient pancreatic cyst identification methodology using natural language processing.

Pancreatic cancer is one of the deadliest cancers, mostly diagnosed at late stages. Patients with pancreatic cysts are at higher risk of developing cancer and their surveillance can help to diagnose the disease in earlier stages. In this retrospective study we collected a corpus of 1064 records from 44 patients at Indiana University Hospital from 1990 to 2012. A Natural Language Processing (NLP) system was developed and used to identify patients with pancreatic cysts. NegEx algorithm was used initially to identify the negation status of concepts that resulted in precision and recall of 98.9% and 89% respectively. Stanford Dependency parser (SDP) was then used to improve the NegEx performance resulting in precision of 98.9% and recall of 95.7%. Features related to pancreatic cysts were also extracted from patient medical records using regex and NegEx algorithm with 98.5% precision and 97.43% recall. SDP improved the NegEx algorithm by increasing the recall to 98.12%.

Preoperative classification of pancreatic cystic neoplasms: the clinical significance of diagnostic inaccuracy.

BACKGROUND: The potential for malignant transformation varies among pancreatic cystic neoplasms (PCN) subtypes. Imaging and cyst fluid analysis are used to identify premalignant or malignant cases that should undergo operative resection, but the accuracy of operative decision-making process is unclear. The objective of this study was to characterize misdiagnoses of PCN and determine how often operations are undertaken for benign, non-premalignant disease. METHODS: A retrospective analysis of patients undergoing pancreatic resection for the preoperative diagnosis of PCN was undertaken. Preoperative and pathological diagnoses were compared to measure diagnostic accuracy. RESULTS: Between 1999 and 2011, 74 patients underwent pancreatic resection for the preoperative diagnosis of PCN. Preoperative classification of mucinous vs. non-mucinous PCN was correct in 74%. The specific preoperative PCN diagnosis was correct in 47%, but half of incorrect preoperative diagnoses were clinically equivalent to the pathological diagnoses. The likelihood that the pathological diagnosis was of higher malignant potential than the preoperative diagnosis was 7%. In 20% of cases, the preoperative diagnosis was premalignant or malignant, but the pathological diagnosis was benign. Diagnostic accuracy and the rate of undercall diagnoses and overcall operations did not change with the use of EUS or during the time period of this analysis. CONCLUSIONS: Precise, preoperative classification of PCN is frequently incorrect but results in appropriate clinical decision-making in three-quarters of cases. However, one in five pancreatic resections performed for PCN was for benign disease with no malignant potential. An appreciation for the rate of diagnostic inaccuracies should inform our operative management of PCN.

Commercial molecular panels are of limited utility in the classification of pancreatic cystic lesions.

The PathfinderTG biomarker panel is useful in the evaluation of pancreatic cysts that have clinical features suspicious for malignancy, but its utility in classifying fine-needle aspiration biopsies from small pancreatic cystic lesions is yet to be proven. We used morphology to classify 20 pancreatic cyst cytology aspirates, all of which met radiographic criteria for close observation. Cases were cytologically classified as consistent with pseudocyst, serous cystadenoma, or mucinous neoplasm with low-grade, intermediate-grade, or high-grade dysplasia and analyzed for carcinoembryonic antigen. Redpath Integrated Pathology Inc. rendered diagnoses of nonmucinous (reactive/indolent or serous) or mucinous (low-risk or at risk) cyst on the basis of results of the PathfinderTG panel (KRAS mutations, DNA content, and loss of heterozygosity at microsatellites linked to tumor suppressor genes). Cytologic and commercial laboratory diagnoses were concordant in only 7 (35%) cases. Seven cysts classified as mucinous with low-grade dysplasia by cytology were interpreted as nonmucinous on the basis of the PathfinderTG panel, 2 of which were resected mucinous cysts. Two pancreatitis-related pseudocysts were misdiagnosed as low-risk mucinous cysts; 1 mucinous cyst with low-grade dysplasia was considered at risk for neoplastic progression using the PathfinderTG panel. Only 1 cyst misclassified as pseudocyst by cytology, but low-risk mucinous cyst by molecular analysis, proved to be a mucinous cystic neoplasm with low-grade dysplasia after surgical resection. We conclude that the PathfinderTG panel may aid the classification of pancreatic lesions, but is often inaccurate and should not replace cytologic evaluation of these lesions.