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Background: Management of pancreatic cysts is based on neoplastic-nonneoplastic discrimination. Endoscopic ultrasound (EUS) enables to differentiate neoplastic-nonneoplastic lesions and also allows fine-needle aspiration (FNA). In this study, we aim to assess feasibility and clinical relevance of cytological and biochemical analysis in differential diagnosis of cystic pancreatic lesions in patients who had undergone endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) due to pancreatic cysts., Methods: Participants were 96 patients who had undergone EUS-FNA for differential diagnosis of pancreatic cysts. Pancreatic cysts were classified as benign-mucinous, nonmucinous, and malignant according to patient history, physical examination, EUS appearance, and cystic fluid assessment. Tumor markers (CEA, CA(cancer antigens) 72.4, CA 19-9) , amylase, lipase and cytological assesment were compared between 3 different groups. Receiver-operating characteristics (ROC) curves were constructed to identify appropriate cut-off values., Results: Fluid CEA and CA 72.4 levels for benign-mucinous and malignant cysts were significantly higher than for nonmucinous cysts (P ≤ 0.04). A cut-off CEA level of 207 ng/mL differentiated mucinous etiology with a sensitivity of 72.7%, specificity of 97.7%, and accuracy of 89.5%. The sensitivity, specificity, and accuracy of the CA 72.4 cut-off level of 3.32 ng/mL were 80%, 69.5%, and 73.6%, respectively., Conclusion: Cyst fluid CEA and CA 72.4 levels have a high accuracy in discriminating mucinous from nonmucinous cysts. When combined with cytology their accuracy rate increases., Competing Interests: The authors have no funding and conflicts of interests to disclose.

Objectives: Endoscopic ultrasonography-guided ethanol ablation therapy for pancreatic cystic lesions is a minimally invasive treatment but still is an experimental therapy. The aims were to investigate the safety and efficacy of endoscopic ultrasonography-guided ethanol ablation therapy., Methods: The inclusion criteria were the following: clinically indeterminate pancreatic cystic lesions in radiologic imaging studies, 2 to 5 cm unilocular or oligolocular cysts without communication to main pancreatic duct, and patients with high-risk operation., Results: There were 91 study patients with median follow-up of 40 months. The response rate was as follows: complete resolution, 41 (45%); partial resolution, 37; and persistent cysts, 13. Pancreatic cystic lesions were categorized based on cystic fluid analysis: 9 intraductal papillary mucinous neoplasms (IPMNs), 12 mucinous cystic neoplasms, 33 serous cystic neoplasms, and 28 uncategorized cysts. The success rate was significantly different according to cystic fluid analysis (serous cystic neoplasm, 58%; mucinous cystic neoplasm, 50%; IPMN, 11%; uncategorized cysts, 39%; P < 0.0001). There were 3 patients with mild pancreatitis after the treatment., Conclusions: Endoscopic ultrasonography-guided ethanol ablation therapy seems to be a safe treatment modality. However, it was only effective in 11% of IPMNs. Therefore, the clinical application should be very limited for certain patients who could not tolerate the surgical treatment.

Peritumoral cyst formation is commonly associated with hemangioblastomas of the central nervous system. Results of a proteomic profiling of hemangioblastoma cyst fluid suggested that cyst formation, whether intratumoral or peritumoral, is a consequence of vascular leakage because protein profiles of cyst fluid and blood serum were similar. To the best of our knowledge, this is the first report of in vivo and ex vivo magnetic resonance spectroscopy analyses of hemangioblastoma cyst fluid that investigates on the mechanism leading to peritumoral cyst formation.

Background: A recently described mucinous non-neoplastic cyst (MNNC) of the pancreas is a benign cyst and should be distinguished from mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN) due to different management and prognosis. The immunoprofile of MNNC has not been well studied., Design: Twenty-three MNNCs diagnosed on surgical resection were retrieved. Immunohistochemical (IHC) staining was performed on surgically resected specimen. Sixteen IPMN and 15 MCN cases were also retrieved for comparison. Cyst fluid carcinoembryonic antigen and amylase concentrations were retrieved., Result: MNNCs were randomly located in the pancreas and were either unilocular or multilocular cysts that were lined by a single layer of bland columnar or cuboidal mucinous cells and supported by paucicellular stroma. The glandular epithelial cells were diffusely positive for CK7 (100%) and PDX-1 (65%); focally positive for CD10 (superficial, 65%), CD99 (basally, 100%), CDX-2 (17%), and CK20 (4%); and negative for MUC2. Only rare stromal cells in the cyst wall were weakly positive for estrogen receptor or progesterone receptor in only 6% of cases and negative for inhibin. These results were also compared with the immunoprofile of IPMN and MCN., Conclusions: Although MNNC shares some IHC markers with IPMN or MCN, an IHC panel can help distinguish MNNC from IPMN or MCN. The results suggest that MNNC is different from IPMN and MCN.

Objectives: Endoscopic ultrasound (EUS) may offer a diagnostic tool through the combination of imaging and guided fine-needle aspiration of pancreatic cysts. The purpose of this investigation was to determine the most accurate test for differentiating mucinous from nonmucinous cysts., Methods: The results of EUS imaging, cytology, and cyst fluid biochemical markers were prospectively collected and compared in a large single-center study (776 patients) using histology or malignant cytology as the final diagnostic standard in 198 patients., Results: The mean cyst fluid carcinoembryonic antigen (CEA) was greater in mucinous cysts (4703.0 ng/mL) compared with nonmucinous cysts (25.8 ng/mL) (P = 0.008). When using the optimal cutoff value of 109.9 ng/mL, the CEA was more accurate (86%, receiver operating characteristic area = 0.928) than EUS imaging (48%) and cytology (58%) in predicting a mucinous cyst (P < 0.0001). Malignant cysts had a mean cyst fluid CEA value (2558.2 ng/mL) similar to benign cysts (4700.2 ng/mL). Cytology (75%) more accurately diagnosed malignant cysts than EUS (66%) and CEA (62%) (P < 0.05)., Conclusions: Cyst fluid CEA concentration provides a highly accurate test for the diagnosis of a mucinous cyst, but does not distinguish benign from malignant cysts. Cytology is the most accurate test for the diagnosis of a malignant cyst.

Objectives: The objective of this study was to evaluate and validate cyst fluid carcinoembyronic antigen (CEA) and amylase in differentiating (1) nonmucinous from mucinous pancreatic cystic lesions (PCLs), (2) benign mucinous from malignant mucinous PCLs, and (3) pseudocysts from nonpseudocysts (amylase only)., Methods: A retrospective analysis of patients with histologically confirmed PCLs from February 1996 to April 2007 was performed. Cyst fluid CEA (n=124) and/or amylase (n=91) were measured and correlated to cyst type., Results: Carcinoembyronic antigen levels (P=0.0001), but not amylase, were higher in mucinous versus nonmucinous cysts. The sensitivity, specificity, and diagnostic accuracy of CEA 200 ng/mL or greater for the diagnosis of mucinous PCLs were 60%, 93%, and 72%, respectively. Carcinoembyronic antigen levels did not differentiate benign from malignant mucinous cysts. Whereas amylase levels were higher in pseudocysts than nonpseudocysts (P=0.009), 54% of noninflammatory PCLs had a level greater than 250 IU/L, including mucinous cystic neoplasms (median, 6800 IU/L; interquartile range, 70-25,295 IU/L). Malignant mucinous cysts had lower amylase levels than benign mucinous cysts (P=0.0008)., Conclusions: Cyst fluid CEA and amylase levels are suggestive but not diagnostic in differentiating PCLs. Unlike CEA, amylase may help differentiate benign from malignant mucinous cysts. Novel biomarkers are needed.

Background and Aims: Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether glycosylation variants on specific proteins in cyst fluid samples could serve as biomarkers to aid in this diagnosis., Methods: We used a novel antibody-lectin sandwich microarray method to measure the protein expression and glycosylation of mucin (MUC)1, MUC5AC, MUC16, carcinoembryonic antigen, and other proteins implicated in pancreatic neoplasia in cyst fluid samples. Fifty-three cyst fluid samples were obtained from patients with mucinous cystic neoplasms (n=17), intraductal papillary mucinous neoplasms (n=15), serous cystadenomas (n=12), or pseudocysts (n=9), with confirmation of histologic diagnosis at surgical resection., Results: The detection of a glycan variant on MUC5AC using the lectin wheat-germ agglutinin discriminated mucin-producing cystic tumors (mucinous cystic neoplasms+intraductal papillary mucinous neoplasms) from benign cystic lesions (serous cystadenomas+pseudocysts) with a 78% sensitivity at 80% specificity, and when used in combination with cyst fluid CA 19-9 gave a sensitivity of 87% at 86% specificity. These biomarkers performed better than cyst fluid carcinoembryonic antigen (37%/80% sensitivity/specificity)., Conclusions: These results demonstrate the value of glycan variants for biomarker discovery and suggest that these biomarkers could greatly enhance the accuracy of differentiating pancreatic cystic tumors. Validation studies will be required to determine the clinical value of these markers.

Background: Many patients with benign serous cystadenoma (SCA) of the pancreas will undergo resection because of the inability to reliably discriminate between SCA and premalignant mucinous cysts (intraductal papillary mucinous neoplasm [IPMN], mucinous cystic neoplasm [MCN])., Methods: Cyst fluid from patients with SCA (n = 15), non main-duct and noninvasive IPMN (n = 32), and noninvasive MCN (n = 12) was aspirated at the time of operative resection and analyzed. Commercially available and custom designed multiplex assays (Luminex) were performed using a biomarker panel developed for pancreatic cancer. Differential protein expression (fluorescence intensity, FI) was compared between the 3 groups for each protein (Wilcoxon rank sum test). Unsupervised sample clustering (hierarchical clustering) and supervised sample classification (prediction analysis for microarrays [PAM]) was then performed., Results: Differential protein expression (P < 0.05) was identified between SCA and IPMN (34/51 proteins, 67%) and between SCA and MCN (13/51 proteins, 25%). The majority of proteins were down-regulated in IPMN and MCN compared with SCA. The only proteins significantly overexpressed in the cyst fluid of patients with mucinous cysts were CEA (median FI: IPMN 11.4, MCN 13.0, SCA 5.3; P < 0.001, IPMN vs. SCA) and CA72.4 (median FI: IPMN 10.4, MCN 10.5, SCA 9.9; P = 0.003, IPMN vs. SCA). Unsupervised cluster analysis demonstrated distinct clustering of SCA and IPMN with some cross-over between MCN. Supervised sample classification with 14 proteins had an overall accuracy rate of 92% between SCA and IPMN., Conclusions: In this study differential cyst fluid protein expression was observed between SCA and IPMN for the majority of proteins assessed and multimarker sample classification accurately discriminated between SCA and IPMN in 92% of patients.

Pleomorphic adenoma (PA) is a rare tumor of the skin that may arise from either the apocrine or the eccrine glands. Only 4 cases of PA in the auricle have been reported. We experienced the case of a 40-year-old woman who had a slowly growing, nontender auricle mass for 3 years. Under a clinical diagnosis of an epidermal inclusion cyst, we performed a total excision of the tumor with the skin and with direct closure. No recurrence was found during the 18 months of postoperative follow-up. Histologic examination confirmed a diagnosis of PA. Hematoxylin-eosin stain showed tubules that were lined with 2 layers of epithelial cells. The stroma was composed of the myxoid and chondroid matrices. Immunohistochemical staining was positive for cytokeratin, epithelial membrane antigen, and gross cystic disease fluid protein, whereas it was negative for S-100 and carcinoembryonic antigen. These findings suggested that this tumor originated from the apocrine glands. Only a few cases of PA in the auricle have been reported in the literature, 2 of which occurred in the helical rim. Recurrence is rare if there is complete resection of the tumor along with the surrounding capsule. We report herein a rare case of PA that developed in the auricle.

Objectives: There are currently no diagnostic indicators that are consistently reliable, obtainable, and conclusive for diagnosing and risk-stratifying pancreatic cysts. Proteomic analyses were performed to explore pancreatic cyst fluids to yield effective diagnostic biomarkers., Methods: We have prospectively recruited 20 research participants and prepared their pancreatic cyst fluids specifically for proteomic analyses. Proteomic approaches applied were as follows: (1) matrix-assisted laser-desorption-ionization time-of-flight mass spectrometry peptidomics with LC/MS/MS (HPLC-tandem mass spectrometry) protein identification; (2) 2-dimensional gel electrophoresis; (3) GeLC/MS/MS (tryptic digestion of proteins fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified by LC/MS/MS)., Results: Sequencing of more than 350 free peptides showed that exopeptidase activities rendered peptidomics of cyst fluids unreliable; protein nicking by proteases in the cyst fluids produced hundreds of protein spots from the major proteins, making 2-dimensional gel proteomics unmanageable; GeLC/MS/MS revealed a panel of potential biomarker proteins that correlated with carcinoembryonic antigen (CEA)., Conclusions: Two homologs of amylase, solubilized molecules of 4 mucins, 4 solubilized CEA-related cell adhesion molecules (CEACAMs), and 4 S100 homologs may be candidate biomarkers to facilitate future pancreatic cyst diagnosis and risk-stratification. This approach required less than 40 microL of cyst fluid per sample, offering the possibility to analyze cysts smaller than 1 cm in diameter.

Objective: Urocortin is a neuropeptide, member of the corticotropin-releasing hormone family, that is produced by the human endometrium. Ovarian endometrioma is a prevalent gynecologic disorder still lacking specific serum markers. In the present study we measured systemic levels of urocortin to assess the diagnostic performance of its determination in distinguishing endometriomas from other benign ovarian cysts., Methods: Plasma urocortin was measured by radioimmunoassay in women with ovarian endometrioma (n=40) and in women with benign, nonendometriotic ovarian cysts (n=40). The diagnostic accuracy of urocortin measurement was evaluated by receiver operating characteristic curve and compared with the standard marker, CA 125. To support the local origin of the peptide, we also evaluated its localization in endometriomas by immunohistochemistry and its concentrations in cyst fluid and peritoneal fluid of 12 women with endometrioma., Results: Plasma urocortin levels were twice as high in women with endometrioma (median 49 pg/mL, interquartile range 41-63 pg/mL) than in the control group (19 [15-23] pg/mL, P<.001) and significantly higher in the cystic content of endometriomas than in the peritoneal fluid and plasma (P<.05). The peptide was immunolocalized in endometrioma glands and stromal capillary vessels. Elevated plasma urocortin levels detected 88% of the cases of endometrioma with 90% specificity, whereas CA 125 detected only 65% of the cases with the same specificity., Conclusion: Plasma urocortin is increased in women with endometriomas, and its measurement may be useful for the differential diagnosis of endometrioma compared with other benign ovarian cysts., Level of Evidence: II.

Objectives: Characterization of pancreatic cysts using endoscopic ultrasound-guided fine-needle aspiration includes cytological interpretation and chemical analysis. We prospectively analyzed the contribution of carcinoembryonic antigen (CEA) and cytological identification of extracellular mucin as predictors of mucinous neoplasia and malignancy., Methods: From January 2003 to October 2005, all patients referred to the University of Virginia with cystic lesions of the pancreas underwent endoscopic ultrasound-guided fine-needle aspiration with cytological evaluation and CEA level analysis. Data were collected prospectively and confirmed by resection or tissue biopsy. Univariate and multivariate analyses were performed on the following variables with regard to their ability to predict mucinous neoplasia: age (<55 or >55 years), sex, CEA level (<300 or >300 ng/mL), and cytological appreciation of extracellular mucin (positive or negative). P values less than 0.05 were considered significant., Results: A total of 43 patients were included in this study. There were 19 men and 24 women with a mean age of 63 +/- 14 years. The only complication was pancreatitis secondary to cyst leak in one patient. Multivariate analysis confirmed CEA level greater than 300 ng/mL (P= 0.007) and the identification of mucin (P < 0.001) as significant predictors., Conclusions: With pancreatic cyst fluid analysis, the strongest predictor of mucinous neoplasia is the presence of identifiable mucin, followed by a CEA level greater than 300 ng/mL. The workup of cystic lesions of the pancreas should include chemical analysis for the CEA level and cytological examination with particular attention to extracellular mucin.

Objective: To describe the ultrasound and MR appearance of paraovarian cystadenomas., Methods: We reviewed retrospectively the radiologic findings in 7 patients with surgically proven paraovarian cystic neoplasms, including 6 serous cystadenomas and 1 borderline seromucinous cystadenoma. All had ultrasound and 4 had MR preoperatively., Results: On ultrasound, the ipsilateral ovary was visualized in six cases, in contact with the cyst in five and separate from it in one. On MR, the ovary and the cyst were visible in four cases, in contact in three and separate in one. Internal papillary excrescences, present at pathology in all cysts, were seen in five on ultrasound and in four on MR., Conclusion: Although the extraovarian location of these neoplasms is difficult to determine preoperatively by ultrasound and MR, these imaging modalities are more reliable in predicting the histology of these rare lesions and differentiating them from simple paraovarian cysts.

Endothelin-1 is a major vasoconstrictor peptide, first found in endothelial cells and later in many other tissues, including the thyroid gland. It is well known that endothelins can act as autocrine and/or paracrine regulators of thyroid homeostasis and growth. Previously we have demonstrated that immunoreactive endothelins (IR-ET) are present in various human body fluids, and IR-ET has also been detected in pathologic breast and thyroid cystic fluids. In this study, the IR-ET in Taiwanese thyroid cystic fluid was measured by radioimmunoassay and characterized by chromatography. Human thyroid cystic fluid was obtained by fine needle aspiration, was centrifuged, and the supernatant was stored at -20 degrees C until IR-ET assay. IR-ET has been detected in 25 of 33 samples of thyroid cystic fluid [25 cases, 4.11 +/- 0.31 fmol/mL (mean +/- standard error of the mean); other eight cases, undetectable]. Gel permeation chromatography of the extract of pooled cystic fluid showed only one major peak at the elution position of human endothelin-1 standard. No difference in cystic IR-ET levels was found in our patients with cystic nodules in relation to differences in thyroid function. It is probable that endothelin-1 is produced by the epithelial cells lining the thyroid cysts, and the increased levels of IR-ET in cystic fluid found in our patients could either be secondary to cystic nodule development or have a role in goiter formation.