Increased incidence of indeterminate pancreatic cysts and changes of management pattern: Evidence from nationwide data.

BACKGROUND: Pancreatic cysts are common. However, most studies are based on data collected from individual centers. The present study aimed to evaluate the changes of management patterns for pancreatic cystic lesions (PCLs) by analyzing large epidemiologic data. METHODS: Between January 2007 and December 2018, information regarding pancreatic cystic lesions was acquired from the nationwide Health Insurance Review and Assessment Service database in Korea. RESULTS: The final number of patients with pancreatic cysts was 165 277 among the total claims for reimbursement of 855 983 associated with PCLs over 12 years. The total number of claims were increased from 19 453 in 2007 to 155 842 in 2018 and the prevalence increased from 0.04% to 0.23%. For 12 years, 2874 (1.7%) had pancreatic cancer and 8212 (5.0%) underwent surgery, and 36 had surgery for twice (total 8248 pancreatectomy). After ruling out claims from the first 3 years of washout period, the incidence increased from 9891 to 24 651 and the crude incidence rate of PCLs expanded from 19.96 per 100 000 to 47.77 per 100 000. Compared to specific neoplasm codes (D136 or D377), the use of pancreatic cyst code (K862) has been remarkably increased and the most common since 2010. The annual number of pancreatectomies increased from 518 to 861 between 2007 and 2012, and decreased to 596 until 2018. The percentage of pancreatic cancer in patients who received pancreatectomy increased from 5.6% in 2007 to 11.7% in 2018. CONCLUSIONS: The incidence of PCLs is rapidly increasing. Among PCLs, indeterminate cyst is increasing outstandingly. A trend of decreasing in the number of resections and increasing cancer rates among resected cysts may be attributed to the updated international guidelines.

Comparison of Preoperative Imaging Modalities for the Assessment of Malignant Potential of Pancreatic Cystic Lesions: A Network Meta-analysis.

PURPOSE: The aims of this study are to compare the performance of various preoperative imaging modalities for assessing the malignant potential of pancreatic cystic lesions (PCLs) through a network meta-analysis (NMA) and to clarify the role of 18 F-FDG PET in the management of patients with PCL. METHODS: PubMed, EMBASE, and Cochrane Library were searched for the studies evaluating the performance of preoperative imaging modalities for identifying malignant PCLs. The NMA was performed for 4 representative categories of various imaging modalities in terms of diagnostic performance for differentiating malignant from benign PCL and intraductal papillary mucinous neoplasms only as a subgroup analysis. To calculate the probability of each imaging modality being the most effective diagnostic method, the surface under the cumulative ranking curve values were obtained. RESULTS: A total of 1018 patients from 17 direct comparison studies using 2 or more preoperative imaging modalities were included for differentiating malignant from benign PCL. The positive predictive value (PPV) and accuracy of 18 F-FDG PET were significantly higher than that of CT (PPV: odds ratio [OR], 2.66; 95% credible interval [CrI], 1.21-6.17; accuracy: OR, 2.63; 95% CrI, 1.41-5.38) or MRI (PPV: OR, 2.50; 95% CrI, 1.09-6.26; accuracy: OR, 2.50; 95% CrI, 1.28-5.47) in all PCLs, as well as in the subgroup analysis for intraductal papillary mucinous neoplasm only. 18 F-FDG PET showed the highest surface under the cumulative ranking curve values in all diagnostic performance areas of sensitivity, specificity, PPV, negative predictive value, and accuracy, followed by MRI or CT. CONCLUSIONS: The results from this NMA suggest that 18 F-FDG PET is the best preoperative imaging modality for differentiating malignant from benign PCLs and that it can be used for the preoperative evaluation of PCLs.

Molecular analysis of cyst fluids improves the diagnostic accuracy of pre-operative assessment of pancreatic cystic lesions.

Pancreatic cystic lesions (PCL) are increasingly diagnosed. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) cytology is often used for diagnostic confirmation but can be inconclusive. In this study, the role of molecular analyses in the pre-operative diagnostics of PCL is evaluated. Targeted Next Generation Sequencing (NGS) applied on cytology smears was retrospectively evaluated in a cohort of 37 resected PCL. Usefulness of NGS on fresh cyst fluids was tested in a prospective cohort of patients with newly diagnosed PCL (n = 71). In the retrospective cohort, cytology plus NGS displayed higher sensitivity (94.1% vs. 87.1%) and specificity (100% vs. 50%) than cytology alone for the detection of mucinous neoplasms. In the prospective cohort, sensitivity and specificity of conventional cytology alone were 54.2% and 100% for the detection of mucinous neoplasia and 50.0% and 100% for the detection of high-grade dysplasia, respectively. Adding NGS, all lesions which underwent histopathologic verification (12/71, 17%) could be classified without false positive or false negative results regarding the detection of mucinous neoplasm so far. NGS analysis of cfDNA in PCL fluids is feasible and can increase diagnostic accuracy in the detection of mucinous neoplasms compared to cytology alone. However, algorithms for the detection of high-risk lesions need further improvement.

Cost-effectiveness of consensus guideline based management of pancreatic cysts: The sensitivity and specificity required for guidelines to be cost-effective.

BACKGROUND: Detection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment. METHODS: We developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended. RESULTS: "Surveillance" using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment ("do nothing"). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and "do nothing." Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than "do nothing" for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided. CONCLUSION: Current management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.

Clinical and Economic Outcomes of Patients Undergoing Guideline-Directed Management of Pancreatic Cysts.

INTRODUCTION: Numerous guidelines exist for the management of pancreatic cysts. We sought to compare the guideline-directed management strategies for pancreatic cysts by comparing 2 approaches (2017 International Consensus Guidelines and 2015 American Gastroenterological Association Guidelines) that differ significantly in their thresholds for imaging, surveillance, and surgery. METHODS: We developed a Monte Carlo model to evaluate the outcomes for a cohort of 10,000 patients managed per each guideline. The primary outcome was mortality related to pancreatic cyst management. Secondary outcomes included all-cause mortality, missed cancers, number of surgeries, number of imaging studies, cumulative cost, and quality-adjusted life years. RESULTS: Deaths because of pancreatic cyst management and quality-adjusted life years were similar in both guidelines at a significantly higher cost of $3.6 million per additional cancer detected in the Consensus Guidelines. Deaths from "unrelated" causes (1,422) vastly outnumbered deaths related to pancreatic cysts (125). Secondary outcomes included more missed cancers in the American Gastroenterological Association guideline (71 vs 49), more surgeries and imaging studies in the Consensus guideline (711 vs 163; 116,997 vs 68,912), and higher cost in the Consensus guideline ($168.3 million vs $89.4 million). As the rate of malignant transformation increases, a more-intensive guideline resulted in fewer deaths related to pancreatic cyst management. DISCUSSION: Our study demonstrates trade-offs between more- and less-intensive management strategies for pancreatic cysts. Although deaths related to pancreatic cyst management were similar in each strategy, fewer missed cancers in the more-intensive surveillance strategy is offset by a greater number of surgical deaths and higher cost. In conclusion, our study identifies that if the rate malignant transformation of pancreatic cysts is low (0.12% annually), a less-intensive guideline will result in similar deaths to a more-intensive guideline at a much lower cost.

Long-Term Assessment of Pancreatic Function After Pancreatectomy for Cystic Neoplasms.

BACKGROUND: With advances in cross-sectional imaging, pancreatic cysts are more frequently diagnosed and have become a common indication for pancreatectomy. The impact of pancreatectomy in these patients is important. The purpose of this study was to assess short-term outcomes, long-term nutritional status, quality of life (QOL), and pancreas function after pancreatectomy for cystic neoplasms. MATERIALS AND METHODS: At a single institution, patients at least 3 y post-pancreatectomy for benign cystic neoplasms were identified. Using a validated questionnaire, short-term outcomes, long-term outcomes including endocrine and exocrine insufficiency, long-term nutritional status, and preoperative and postoperative QOL were compared based on operation and indication for resection. RESULTS: Among 102 eligible patients, 70 had valid contact information and 51 (72.9%) agreed to participate. Median follow-up was 6 (4-8) y. Patients undergoing pancreatoduodenectomy for benign cysts had higher morbidity than a similar cohort resected for pancreatic adenocarcinoma (patients with at least 1 ≥ grade 2 complication [49.0% versus 31.6%, P = 0.038]). After long-term follow-up, pancreatectomy did not significantly affect perceived QOL. Half of patients had mild-moderate or severe malnourishment, but pancreatic enzyme replacement was reported by only 4 (7.8%) patients. New-onset diabetes was present in 15 (29.4%) patients with median time-to-diagnosis of 6 (1-12) mo after resection. CONCLUSIONS: Pancreatectomy for benign cysts did not negatively impact patients' perceived QOL. However, after long-term follow-up, malnutrition and pancreatic insufficiency occurred in a significant percentage and may be greater than previously estimated. Consideration of short- and long-term outcomes should factor into preoperative counseling, especially in cysts with minimal risk of progression to malignancy.

National trends in resection of cystic lesions of the pancreas.

BACKGROUND: Management of cystic lesions of the pancreas (CLP) is controversial. In this study, we sought to evaluate national changes in the resection of CLP over time, to better understand the impact of evolving guidelines on CLP management. METHODS: We used Medicare data to examine CLP resection among patients undergoing pancreatic resection between 2001 and 2012. Patients with a diagnosis of CLP were identified and compared to patients with non-CLP indications. We then examined changes over time in patient and hospital characteristics and outcomes among patients with a CLP diagnosis. RESULTS: We identified 56,419 Medicare patients undergoing pancreatic resection, of which 2129 had a CLP diagnosis. The annual number of CLP resections, and proportion of all resections performed for CLP increased significantly during the period, from 2.1% (65/3072) resections in 2001, to 4.5% (286/6348) in 2012 (p < 0.001). The proportion of CLP resections with a malignant diagnosis did not change (15.5% in 2001-2003 vs. 13.1% in 2010-2012, p = 0.4). Overall rates of 30-day mortality decreased significantly during the period (9.6% in 2001-2003 vs. 5.5% in 2010-2012, p < 0.001). DISCUSSION: CLP resections were performed with increasing frequency in Medicare patients between 2001 and 2012, but this did not correspond to increased diagnosis of malignancy. Additional research is needed to understand the influence of recent guidelines on management of CLP.

Cytologic categorization of pancreatic neoplastic mucinous cysts with an assessment of the risk of malignancy: A retrospective study based on the Papanicolaou Society of Cytopathology guidelines.

BACKGROUND: Cytology plays a pivotal role in the preoperative diagnosis of pancreatic cysts. Here the Papanicolaou Society of Cytopathology (Pap Society) guidelines were used to reclassify and assess the malignancy risk of cytology diagnoses of histologically proven pancreatic neoplastic mucinous cysts. METHODS: A database search (January 2000 to June 2014) was performed for pancreatic neoplastic mucinous cyst resections with endoscopic ultrasound-guided fine-needle aspiration within the preceding year. Histologic diagnoses were reclassified according to the 2010 Word Health Organization criteria. For atypical/suspicious/positive cytology diagnoses, the cytology slides were reviewed, blinded to the histologic diagnoses. The cysts were reclassified according to the Pap Society guidelines, and the findings were correlated with the histology. RESULTS: One hundred thirty-eight cases of pancreatic neoplastic mucinous cysts were retrieved. Eleven cases with atypical/suspicious cytology diagnoses with unavailable slides were excluded. The remaining 127 cases included 81 intraductal papillary mucinous neoplasms and 46 mucinous cystic neoplasms. The sensitivity of cytology for the diagnosis of neoplastic mucinous cysts was 76.4%. The sensitivity, specificity, and accuracy of cytology for the diagnosis of malignancy (high-grade dysplasia or worse) were 48.3%, 94.9%, and 84.3%, respectively. The risk of malignancy was 17.4% for the nondiagnostic category, 0% for the negative category, 13% for the neoplastic category, 63.6% for the atypical category, 80% for the suspicious category, and 100% for a positive diagnosis. CONCLUSIONS: This study reveals that the Pap Society guidelines allow the accurate categorization of pancreatic neoplastic mucinous cysts with cytology. The diagnostic categories (from negative to positive) are associated with an increasing risk of malignancy, and this can further aid in patient management and risk stratification.

Prevalence, Diagnosis and Management of Pancreatic Cystic Neoplasms: Current Status and Future Directions.

Cystic neoplasms of the pancreas are found with increasing prevalence, especially in elderly asymptomatic individuals. Although the overall risk of malignancy is very low, the presence of these pancreatic cysts is associated with a large degree of anxiety and further medical investigation due to concerns about malignancy. This review discusses the different cystic neoplasms of the pancreas and reports diagnostic strategies based on clinical features and imaging data. Surgical and nonsurgical management of the most common cystic neoplasms, based on the recently revised Sendai guidelines, is also discussed, with special reference to intraductal papillary mucinous neoplasm (IPMN; particularly the branch duct variant), which is the lesion most frequently identified incidentally. IPMN pathology, its risk for development into pancreatic ductal adenocarcinoma, the pros and cons of current guidelines for management, and the potential role of endoscopic ultrasound in determining cancer risk are discussed. Finally, surgical treatment, strategies for surveillance of pancreatic cysts, and possible future directions are discussed.

Comparison of endoscopic ultrasound and computed tomography in the assessment of pancreatic cyst size using pathology as the gold standard.

BACKGROUND/OBJECTIVES: Accurate assessment of whether a cyst is greater than 3 cm is an essential component when considering resection especially for mucinous lesions. The most accurate method of assessing cyst size is uncertain with many patients undergoing several complimentary imaging modalities. This study aimed to compare the accuracy of endoscopic ultrasound (EUS) with CT scanning in assessing pancreatic cyst size compared to histology. METHODS: Patients referred for EUS of a pancreatic cystic lesion from April 2003 to August 2011. Patient age and gender, lesion size and site were recorded and compared using cyst size at histology compared to EUS and CT recorded within 3 months of surgery. Subgroup analysis was performed with respect to cyst site and proven mucinous lesions. RESULTS: 357 patients were included of which 70 (mean age 60.6 years, 24 males) had undergone surgical resection. The resected cysts were located 30/17/23 in the head/body/tail of the pancreas. Median size at histology was 32 mm compared to 35 mm at EUS (p = 0.47) and 35 mm at CT (p = 0.52). For mucinous lesions alone, median size at histology was 32 mm compared to 33 mm at EUS (p = 0.46) and 35 mm at CT (p = 0.39). EUS and CT had comparable sensitivity, specificity, negative predictive value, positive predictive value and accuracy for all cyst types and locations. CONCLUSIONS: CT and EUS measurements are not significantly different to pathological size following resection of pancreatic cystic lesions. CT and EUS are interchangeable investigations for determining cyst size pre-operatively although EUS has the additional advantage of fluid sampling.

The role of cytology in the preoperative assessment and management of patients with pancreaticobiliary tract neoplasms.

OBJECTIVE: Endoscopic ultrasound-guided fine-needle aspiration and bile duct brushings are utilized in the cytologic evaluation of solid and cystic pancreaticobiliary tract lesions. We sought to determine the diagnostic accuracy of cytology. METHODS: Five hundred seventy-nine pancreatic resections with 727 corresponding cytology specimens were identified from 1997 to 2012. Histologic diagnoses included benign, carcinoma, pancreatic endocrine neoplasm (PEN), nonepithelial neoplasms, cystic neoplasms, and ampullary adenomas. Standard interpretative categories-nondiagnostic, negative, atypical, suspicious, and positive--were utilized for preoperative cytology specimens. RESULTS: For solid masses, the sensitivity and specificity of positive fine-needle aspiration (FNA) cytology for detecting carcinoma were 74 and 100 %, respectively. FNAs performed better than brushings (sensitivity, 40 %; specificity, 98 %) in detecting carcinomas. Similar findings were seen for PENs and nonepithelial neoplasms. For cystic lesions, the sensitivity of FNA for predicting malignancy was lower (24 %) with a specificity of 97 %. Sequentially combining suspicious and atypical categories with the positive category resulted in increases in sensitivity and decreases in specificity for all cases except for cystic lesions. CONCLUSIONS: Cytology adds to the assessment of solid masses, but its utility in cystic lesions is less clear. Consideration of a suspicious cytologic interpretation as a positive diagnosis for triaging patients to surgery is supported by our study.

Optimizing management of pancreatic cysts--prospective re-assessment for 157 cases.

BACKGROUND/AIMS: Ongoing debate continues regarding the appropriate management of pancreatic cysts (PCs). Disagreement prevails regarding frequency of needed follow-up, if and when to perform any PC needle biopsy and indications for surgical resection. EUS is increasingly used to help determine management of PCs. METHODOLOGY: One hundred and fifty seven consecutive patients with PCs were identified out of 5000 patients who underwent EUS between 1995-2007. In 2008, these patients were then prospectively provided clinical follow-up, and CEA, CA19-9 and CRP. RESULTS: No symptoms could be definitively related to the PCs. Twenty four of 157 patients with suspected malignant cysts, mucinous cysts or IPMN had undergone surgical treatment. Whipple's operation was performed in 14 patients and distal pancreatectomy in 10 patients. Fifty PCs were located in the head of pancreas. In 89 patients prospective blood tests were performed; in 6 of them elevated levels of CA-19-9 were detected, 3 of these also had elevated serum CEA. Twelve patients had increased CRP values. No complication (requiring hospitalization) and no mortality related to EUS had occurred. CONCLUSIONS: Elements identified as important for assessment of PCs included: size, serum and fluid markers, imaging characteristics and clinical follow-up. These factors should be included in the recommended guidelines.

Asymptomatic pancreatic cysts: a decision analysis approach to observation versus resection.

OBJECTIVES: Pancreatic cysts are being found with increasing frequency. Although symptomatic cysts should be resected, what to do about asymptomatic cysts is less clear. The purpose of this study was to determine threshold values to choose resection over observation for a patient with an asymptomatic pancreatic cyst. METHODS: Decision analysis assesses the consequences of a decision based on occurrence probabilities. This decision analysis assessed 1 decision, to resect or observe a patient with an asymptomatic pancreatic cyst. The consequences for resection are operative mortality/no operative mortality, short-term morbidity of patients surviving the operation, benign/malignant cyst, and life expectancy after resection of malignant lesions. The probabilities are based on the extant literature. The age-specific life expectancy for benign cysts was considered the same as for the general age-specific population from the 2002 United States Life Table. Because the operative mortality, distribution of benign versus malignant cysts, and life expectancy after resection or observation for malignant cysts vary, sensitivity analysis was done to assess the threshold values of these factors when resection becomes favored over observation. RESULTS: The baseline decision analysis is based on the following assumptions: 30% of lesions are malignant, operative mortality rate is 3%, and the 5-year survival rate of resected malignant cysts is 50%. Varying on age, the risk of the cystic lesion being malignant to favor resection is greater than 11.6% to 15.5%, the operative mortality rate has to be less than 7.4% to 13.8%, and the life expectancy gain by resecting, rather than observing a malignant lesion, has to be greater than 3.49 to 5.38 years. CONCLUSIONS: The decision to resect must be based on the surgeon's operative mortality rate, the predicted operative mortality for the individual patient, the probability that the lesion is malignant, and the survival difference between resecting and observing malignant cystic lesions. Overall, for resection to be recommended, the physician must believe that the risk that the lesion is malignant is approximately 15% or greater, that the life expectancy gained from resection be approximately 5 years or greater, and that the surgeons' operative mortality rate be approximately 8% or less.

Preoperative evaluation of pancreatic cystic lesions: cost-benefit analysis and proposed management algorithm.

BACKGROUND: This study was performed to develop a management algorithm that accurately predicts the necessity of operative intervention and results in significant cost savings for patients with cystic pancreatic tumors. METHODS: We reviewed 60 patients treated between 1992 and 2003. Accuracy rates of tests used to differentiate benign from premalignant and malignant cysts were calculated. A management algorithm was generated that incorporated clinical presentation, radiologic findings, and selective use of endoscopic procedures. This algorithm was tested for predictive accuracy, and savings between actual management and proposed management were compared. RESULTS: There was an average of 3 preoperative tests performed per patient. Endoscopic procedures included endoscopic retrograde cholangiopancreatography in 21 patients and endoscopic ultrasound in 25 patients. A cyst fluid carcinoembryonic antigen (CEA) level of 158 ng/mL or greater had an accuracy rate of 87.5% that was significantly higher than endoscopic retrograde cholangiopancreatography (72%), endoscopic ultrasound morphology (45%), or endoscopic ultrasound cytology (66.7%). There was no combination of tests that provided greater accuracy than cyst fluid CEA level alone (P < .05). The management algorithm had a positive predictive value of 81%. The average actual cost of radiographic and endoscopic procedures was dollar 8,080 per patient. The proposed cost based on the algorithm was dollar 6,677 with a savings of dollar 1,403 per patient (P = .009). CONCLUSIONS: In patients with clinical symptoms or radiographic findings of mucinous or malignant tumors, further testing is excessive. Of endoscopic tests available, the cystic fluid CEA level most accurately predicts the presence of a mucinous neoplasm. A management algorithm based on presenting symptoms, radiographic findings, and cyst fluid CEA level provides a guideline for the evaluation of cystic lesions in the most cost-efficient manner while ensuring proper care.

Cyst fluid analysis in the differential diagnosis of pancreatic cysts: a new approach to the preoperative assessment of pancreatic cystic lesions.

Pancreatic cysts include pseudocysts, serous tumors, and mucinous tumors, some of which are malignant. The clinical and radiologic features of these lesions may not permit a preoperative diagnosis. Analysis of percutaneous cyst fluid aspirates for cytologic findings, tumor markers, enzymes, and viscosity has been proposed as an aid to differential diagnosis. The combination of cytologic findings, carcinoembryonic antigen level, and viscosity will usually differentiate mucinous from nonmucinous cysts, whereas cytologic findings and levels of tumor markers CA 15-3 and CA 72-4 are useful to predict malignancy. Pseudocysts can be identified by a combination of cytologic features; levels of tumor markers, including NB/70K; and levels of enzymes, including amylase isoenzymes and leukocyte esterase. Serous tumors are a diagnosis of exclusion, although in 50% of cases the cytologic findings will indicate a serous tumor. When compared with conventional methods of differentiating pancreatic cysts, cyst fluid analysis is a promising new approach to the evaluation of these diagnostically difficult lesions.

Papillary cystic tumors of the pancreas. Assessment of their malignant potential.

BACKGROUND: Although the biologic characteristics of papillary cystic tumors (PCT) generally indicate a good prognosis, a malignant form has been reported. METHODS: Twenty-two examples of PCT were examined to assess their malignant potential by histologic, flow cytometric, and immunohistochemical studies. RESULTS: Three had hepatic, peritoneal, and/or lymph node metastases (metastasizing tumors [MT]); the other 19 PCT had no such metastatic features (nonmetastasizing tumors [NMT]). Venous invasion was detected in all three MT and two NMT. Compared with the 19 NMT, the MT had a higher nuclear grade and more prominent necrobiotic nests characterized by aggregates of cells with pyknotic nuclei and eosinophilic cytoplasm. In the flow cytometric analysis of cellular DNA content, one MT was aneuploid, and eight NMT were diploid. Immunohistochemically, there was no difference between the MT and NMT. CONCLUSIONS: These results support the assumption that venous invasion, nuclear grade, and prominent necrobiotic nests are useful as histologic parameters to detect the malignant potential of PCT.