Pancreatic Cyst. Introduction. EUS Findings of Pancreatic Cysts. Symposium

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1 Symposium Symposium II - Pancreatobiliary System : Endoscopic Approach for the Early Detection of Pancreatobiliary Malignancy in Ji Kon Ryu Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Introduction Pancreatic cysts are being detected with increasing frequency, at least partly because of the increased use of cross-sectional imaging for the evaluation of abdominal complaints or screening for other conditions. 1 Pancreatic cysts are a large group of varying entities, with a wide variability of biological behavior, from benign to borderline to malignant. In an experienced, high-volume center, preoperative diagnosis was incorrect in one-third of incidentally discovered pancreatic cysts who underwent resection. 2 Overall, in only 68% of cases did the preoperative and histological diagnoses match. A unique property of endoscopic ultrasonography (EUS) is the detailed imaging of pancreas and EUS proved an accurate imaging modality for the pancreas. The introduction of curvilinear-array echoendoscopes and cyst aspiration and cytology by EUS-guided fine needle aspiration (EUS-FNA) highly upgraded the diagnostic value of EUS in the pancreatic cyst. In this review, I will introduce typical findings of each cystic neoplasm and analyze endoscopic approach, with particular attention on the EUS aspect for the early detection of premalignant or malignant cysts. EUS Findings of s With EUS, it is possible to define cystic localization, size, locularity, internal structural features, mural nodules, contours, cystic wall, pancreatic duct and calcification. One of the problems with this technique related to the morphological aspects of pancreatic cystic lesions is the plurality of terms used by different authors to define them. Locularity is determined by the presence of septa and can be classified as unilocular (or monolocular) or multilocular (or multicystic). The cystic component can be classified with microcystic area or without microcystic area. The microcystic area is defined as an area where small (less than 2-3 mm each) cysts aggregate (usually more than 6 cysts) separated by thin-walled septa, producing a honeycomb-like appearance. The contour can be round (or ovoid), lobulated or irregular. 3 Lobulated is defined as the presence of rounded contours that cannot be described as the borders of the same circle. Irregular is defined as the presence of high irregularity in the contours. The wall cyst is considered thin if it is 2 mm or less and thick if more than 2 mm for at least 25% of the lesion circumference Serous Cystadenoma (SCA) Visualization of the microcystic area within the cyst, located either at the centre of the cyst or next to a macrocystic area or in the internal septa of the lesions, is very typical of these lesions. 4,5 The best modality for depicting this aspect is EUS. The microcystic area is present in about 85% of SCAs and is highly accurate in the specific diagnosis of this lesions. 3 A central stellate scar (sunburst), sometimes calcified, is pathognomonic but is seen in 20%-30%. In lesions in which the cysts are a few millimeters in size, the tumor can have a solid appearance due to innumerable interfaces. Unilocular SCAs with no microcystic component account for about 10% of all these lesions. The only characteristics that can help in identifying these is the absence of a discernible cystic wall and lobulated contour, although in this case a more reliable diagnostic Clin Endosc Vol. 45 Suppl 1, nd Congress of the Korean Society of Gastrointestinal Endoscopy S33

2 tool is analysis of cystic fluid. 6,7 2. Mucinous Cystic Neoplasm (MCN) They are a well defined, single, round (orange like) cyst that can be unilocular but more typically present with multiple macrocystic locules (usually less than 6, which are usually > 1-2 cm in diameter divided by septa and with no macroscopic communication with the pancreatic duct. 6,7 The aspect is of a cysts in cyst. MCNs commonly have a visible cystic wall (> 2 mm). Thick mucoid cyst content can appear granulated on EUS. Peripheral wall curvilinear calcifications (egg shell calcification) are characteristic of these lesions, although present in less than 10%-25% of cases, and are considered predictive of malignancy. 7,8 Focally thickened cystic wall or internal septa, clear intramural nodules or solid component, and dilation of the pancreatic duct are associated with invasive malignancy. Goh et al. reported that none of the 40 malignant (carcinoma in situ or invasive) MCNs in his study were < 3 cm; only one was < 4.5 cm (3 cm). 8 In a study by Crippa et al., all MCNs with cancer were either 40 mm in size or had nodules Intraductal Papillary Mucinous Neoplasm (IPMN) Branch duct (BD)-IPMNs need differential diagnosis with other pancreatic cystic lesions. Main duct (MD)-IPMNs most need differential diagnosis with chronic pancreatitis. The typical aspect of BD-IPMNs is mutiloculated lesion, with a bunch of grapes aspect, produced by multiple secondary pancreatic ducts dilated by mucin. So these aspects produce two important image characteristics of these lesions: firstly, the lesions have different from MCNs, which have a cyst in cyst aspect. In addition, these lesions do not have a round shape, but do have an irregular contour. However, these lesions are sometimes formed by only one large ectatic pancreatic secondary duct and in this case the lesions will be unilocular, round and impossible to distinguish from other unilocular pancreatic cystic lesions by EUS aspect only. One of the most important diagnostic tools for BD-IPMNs is identifying whether there is communication between the lesion and the pancreatic duct. During EUS exams, an endoscopic view of the papilla should be always done to exclude mucin extruding from the patulous papilla (fish mouth papilla), which is diagnostic of IPMNs, although this phenomenon is present in only 30% of cases. Pais et al. showed that in 74 operated patients, EUS features of a solid lesion, a dilated main pancreatic duct, ductal filling defects and thickened septa were predictive of malignancy in IPMNs. 10 In another study, main pancreatic duct dilatation (over than 1cn) and solid mass in EUS suggested the malignancy with 70% accuracy. The international consensus guidelines for management of intraductal papillary mucinous neoplasm was reported in Cysts with obvious high-risk stigmata on CT or MRI (obstructive jaundice in a patient with a cystic lesion of the pancreatic head, enhanced solid component, main pancreatic duct size over than 10 mm) should undergo resection without further testing. Worrisome features on imaging include cyst size over than 3 cm, thickened enhanced cyst walls, main pancreatic duct size of 5-9 mm, non-enhanced mural nodules, abrupt change in the main pancreatic duct caliber with distal pancreatic atrophy, and lymphadenopathy. All smaller cysts with worrisome features should be evaluated by EUS to further risk-stratify the lesion. Patients with cysts of >3 cm and no worrisome features can also be considered for EUS to verify the absence of thickened walls or mural nodules, particularly if the patient is elderly. Surgical resection should be considered if any of three features including definite mural nodule, main duct feature suspicious for involvement, suspicious for malignancy in cytology. Differential diagnosis is important between mural nodule and mucin. Studies relying on CT and MRI show a relationship between mural nodules and malignancy, 13,14 but studies primarily using EUS do not confirm this finding. However, recent study demonstrated that mural nodules in pancreatic cysts are predictors of malignancy and the accuracy for detecting mural nodule is better in EUS than CT. 15 Cancer or high-grade dysplasia was found in 23% of cysts with nodules versus 3% without nodules. EUS detected epithelial nodules with 75% sensitivity and 83% S34 62 nd Congress of the Korean Society of Gastrointestinal Endoscopy Clin Endosc Vol. 45 Suppl 1, 2012

3 Ji Kon Ryu specificity, whereas these values were 24% and 100%, respectively, for CT. Most echogenic lesions seen in cysts during EUS are mucus, not true epithelial mural nodules. Three EUS features discriminate mucus from mural nodules in pancreas cysts; mucus is usually hypoechoic compared with adjacent soft tissue, smooth-edged, and has a hyperechoic rim. Mural nodules are usually isoechoic or hyperechoic compared with adjacent soft tissue, are not smooth-edged, and do not have a hyperechoic rim. The diagnostic accuracy of the raters improved up to 90% when all 3 features of mucus were present. In addition, body position change and EUS FNA are useful for distinguishing mucus from mural nodules during EUS. A few studies suggested that contrast-enhanced EUS were useful for the detection of true mural nodule and predicting malignant protection of IPMN. 14 However, further confirmative study is needed to confirm the value of it. One study assessed the degree of interobserver agreement in the morphological characterization of pancreatic cysts, by means of EUS video sequences. 16 When the Intraclass Correlation Coefficient (ICC) was used, agreement regarding specific diagnosis was moderate (ICC 0.52) in the expert group. Agreement regarding nodules was good (ICC 0.65) among experts and it means that nodule is the most objective findings. However, interobserver agreement for semi-experts was lower than expert group. 4. Other cystic tumor One percent of pancreatic cancer can be manifested as cystic mass due to cystic degeneration and it is called as cystic ductal adenocarcinoma. Due to the central necrosis, the mass seems to be unilocular cyst but mass usually are surrounded with malignant tissue. Sometimes, cystic ductal adenocarcinoma can be misdiagnosed as pseudocyst. Even if pancreatic neuroendocrine tumors are solid mass, it can be also manifested as cystic mass due to cystic degeneration. For the differential diagnosis, EUS fine needle aspiration (FNA) is necessary for cytology examination and usually helpful. Cyst Fluid Aspiration A review of seven studies about the diagnostic accuracy of EUS morphology in differentiating cystic lesions of the pancreas, reported results of between 51% and 90%. 17 It means that the sensitivity and specificity for the differential diagnosis of pancreatic cyst was variable and not high. Recent prospective study reported that sensitivity for diagnosing a mucinous cyst was 78% for EUS versus 91% for MRI. Sensitivity for detecting malignancy was 25% and 50% for EUS and MRI respectively. 11,13 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. 11 EUS can be recommended when usual radiologic findings is not typical for each cystic neoplasm, however, EUS features are sometimes very difficult for definite diagnosis. EUS- FNA and cyst fluid examination can be helpful in indeterminate cyst. EUS-FNA allows evaluation of extracellular mucin, cytological and sometimes histological analysis, biochemical, tumor markers and molecular analysis. CEA is considered the most accurate marker in differentiating mucinous from non-mucinous cysts. There is continual debate in the literature over the best cut-off of CEA levels for discriminating mucinous from non-mucinous cysts. The value of cut-off ranges from 20 ng/ml to 800 ng/ml in different studies, obviously with greater sensitivity for a low cut-off value and greater specificity for higher ones. However, the most frequently utilized cut-off derives from a large prospective study by Brugge et al. on 112 patients who underwent surgery. 18 They established that a level of 192 ng/ml has a diagnostic sensitivity of 75%, a specificity of 84% and an accuracy of 79% in differential diagnosis of mucinous and non-mucinous cysts. In another pooled analysis from 12 studies, a value of > 800 ng/ml arrived at a specificity of 98%, but a sensitivity of only 48%. 19 The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of a CEA level Clin Endosc Vol. 45 Suppl 1, nd Congress of the Korean Society of Gastrointestinal Endoscopy S35

4 >200 ng/ml for the diagnosis of malignant IPMNs were 90%, 71%, 50%, and 96%, respectively. 20 However, the recent study reported that the degree of cyst fluid CEA elevation is a poor predictor of malignant degeneration within IPMNs. 21 A meta-analysis comparing EUS-FNA-based cytology with surgical biopsy or histology and including 376 patients from eleven studies showed a low sensitivity (63%), but good specificity (88%) in differentiating mucinous cystic lesions from non-mucinous lesions, with a diagnostic accuracy of 89%. 22 The largest prospective study of FNA cytology showed a sensitivity, specificity and accuracy of 34.5%, 83% and 51%, respectively. 23 EUS-FNA was possible in 90% of patients but cytological diagnosis was obtained in only 31%, due to insufficient cellularity of aspirate liquid. 23 Recent study reported the accuracy of cytology in resected IPMN. 24 EUS-FNA demonstrated malignancy in only 21 (54 %). An additional seven (18 %) had EUS-FNA findings of atypia or concern for mucinous neoplasm. A recently published prospective study described techniques for obtaining more cellularity for cytological diagnosis. This technique consists of attempting to obtain a Cystic Wall Biopsy (CWB) by puncturing the far wall of the cyst and moving the needle back and forth through the wall, after aspiration of fluid from the cyst. The author reports that 81% of the specimens had cellular material adequate for cytological assessment, which was higher than has previously been reported for standard FNA. 25 Although Echobrush (19G Cook Medical) showed better results, technical success rate was 73% and it can only be used for lesions that are at least 2 cm in diameter and a high rate of complications (8%-10%). 26 K-ras mutation analysis in cyst fluid might increase the sensitivity and specificity for prediction of mucinous cyst but high cost and availability pose some limits. 27 Experimental Method An alternative or adjunct to cyst wall cytology might be to directly examine the cyst wall. There have also been reports using the optical catheter used in the Spyglass system to directly visualize the cyst lining. The optical fiber is passed down a 19G needle after puncturing the cyst. Aparicio et al. reported successful visualization of the cyst lining in 2 patients. 28 Both patients also underwent forceps biopsies thru the 19G needle. There have been recent reports of using a small confocal microscopy probe. Konda et al. reported use of this technology on 18 patients. 29 The images were considered to be high quality. This preliminary study demonstrated feasibility. Conclusions There is no single test accurate enough to make a sure diagnosis in every pancreatic cystic lesion and so the diagnosis of such lesions is a puzzle, with bits of information deriving from demographic, clinical, radiological, EUS morphological findings and intracystic fluid analyses. EUS morphology alone cannot provide for a sure diagnosis in all cases and a recently published paper on inter observer agreement confirms that such agreement is generally low. Therefore, we should keep in mind the typical findings of each cystic tumor, especially MCN, IPMN and the true mural nodule predicting malignant potential. In atypical case with indeterminate pancreatic cyst, EUS-FNA and cyst fluid analysis may be helpful. In general, cytology in every study showed low sensitivity and high specificity, allowing, when positive, to predict the type of lesion. CEA showed good accuracy for differentiation between mucinous and nonmucinous cyst, but there is continual debate in the literature over the best cut-off of CEA levels. Further endoscopic approach should be developed even if there are some preliminary studies. References 1. Balthazar EJ, Chako AC. Computed tomography of pancreatic masses. Am J Gastroenterol 1990;85: S36 62 nd Congress of the Korean Society of Gastrointestinal Endoscopy Clin Endosc Vol. 45 Suppl 1, 2012

5 Ji Kon Ryu 2. Correa-Gallego C, Ferrone CR, Thayer SP, Wargo JA, Warshaw AL, Fernández-Del Castillo C. Incidental pancreatic cysts: do we really know what we are watching? Pancreatology 2010; 10: Kubo H, Nakamura K, Itaba S, Yoshinaga S, Kinukawa N, Sadamoto Y, Ito T, Yonemasu H, Takayanagi R. Differential diagnosis of cystic tumors of the pancreas by endoscopic ultrasonography. Endoscopy 2009; 41: Gouhiri M, Soyer P, Barbagelatta M, Rymer R. Macrocystic serous cystadenoma of the pancreas: CT and endosonographic features. Abdom Imaging 1999;24: Jung SW, Lee SS, Kim KP, et al. Can EUS Help to Differentiate Macrocystic Serous Cystadenoma from Mucinous Cystadenoma of the Pancreas by Its Morphologic Characteristics? Korean J Gastrointest Endosc 2006;32: Gress F, Gottlieb K, Cummings O, Sherman S, Lehman G. Endoscopic ultrasound characteristics of mucinous cystic neoplasms of the pancreas. Am J Gastroenterol 2000;95: Barresi L, Tarantino I, Granata A, Curcio G, Traina M. Pancreatic cystic lesions: How endoscopic ultrasound morphology and endoscopic ultrasound fine needle aspiration help unlock the diagnostic puzzle. World J Gastrointest Endosc Jun 16;4(6): Goh BK, Tan YM, Chung YF, et al. A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients. World J Surg 2006; 30: Crippa S, Salvia R, Warshaw AL, et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg 2008; 247: Pais SA, Attasaranya S, Leblanc JK, Sherman S, Schmidt CM, DeWitt J. Role of endoscopic ultrasound in the diagnosis of intraductal papillary mucinous neoplasms: correlation with surgical histopathology. Clin Gastroenterol Hepatol 2007; 5: de Jong K, van Hooft JE, Nio CY, et al. Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions. Scand J Gastroenterol. 2012;9: Tanaka M, Castillo CF, Adsay V, et al. International consensus guidelines 2012 for the Management of IPMN and MCN of the pancreas. Pancreatology 2012;183: Mimura T, Masuda A, Matsumoto I, et al. Predictors of malignant intraductal papillary mucinous neoplasm of the pancreas. J Clin Gastroenterol 2010;44:e224-e Ohno E, Hirooka Y, Itoh A, et al. Intraductal papillary mucinous neoplasms of the pancreas: differentiation of malignant and benign tumors by endoscopic ultrasound findings of mural nodules. Ann Surg 2009;249: Zhong N, Zhang L, Takahashi N, et al. Histologic and imaging features of mural nodules in mucinous pancreatic cysts. Clin Gastroenterol Hepatol. 2012;10: de Jong K, Verlaan T, Dijkgraaf MG, et al. Interobserver agreement for endosonography in the diagnosis of pancreatic cysts. Endoscopy 2011;43: Oh HC, Kim MH, Hwang CY, Lee TY, Lee SS, Seo DW, Lee SK. Cystic lesions of the pancreas: challenging issues in clinical practice. Am J Gastroenterol 2008; 103: Khalid A, Zahid M, Finkelstein SD et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc 2009;69: van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions:a pooled analysis. Gastrointest Endosc 2005; 62: Maire F, Voitot H, Aubert A, et al. Intraductal papillary mucinous neoplasms of the pancreas: performance of pancreatic fluid analysis for positive diagnosis and the prediction of malignancy. Am J Gastroenterol. 2008;103: Kucera S, Centeno BA, Springett G,et al. Cyst fluid carcinoembryonic antigen level is not predictive of invasive cancer in patients with intraductal papillary mucinous neoplasm of the pancreas. JOP ;13: Thosani N, Thosani S, Qiao W, Fleming JB, Bhutani MS, Guha S. Role of EUS-FNA-based cytology in the diagnosis of mucinous pancreatic cystic lesions: a systematic review and meta-analysis. Dig Dis Sci 2010; 55: de Jong K, Poley JW, van Hooft JE, Visser M, Bruno MJ, Fockens P. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. Endoscopy 2011;43: Wong J, Weber J, A Centeno B, et al. High-Grade Dysplasia and Adenocarcinoma Are Frequent in Side-Branch Intraductal Papillary Mucinous Neoplasm Measuring Less than 3 cm on Endoscopic Ultrasound. J Gastrointest Surg Sep 5. [Epub ahead of print] 25. Hong SK, Loren DE, Rogart JN,et al. Targeted cyst wall puncture and aspiration during EUS-FNA increases the diagnostic yield of Clin Endosc Vol. 45 Suppl 1, nd Congress of the Korean Society of Gastrointestinal Endoscopy S37

6 premalignant and malignant pancreatic cysts. Gastrointest Endosc. 2012;75: Sendino O, Fernández-Esparrach G, Solé M, et al. Endoscopic ultrasonography-guided brushing increases cellular diagnosis of pancreatic cysts: A prospective study. Dig Liver Dis. 2010;42: Sawhney MS, Devarajan S, O Farrel P, et al. Comparison of carcinoembryonic antigen and molecular analysis in pancreatic cyst fluid. Gastrointest Endosc 2009; 69: Aparicio JR, Martinez J, Niveiro M, et al. Direct intracystic biopsy and pancreatic cystoscopy through a 19-gauge needle EUS (with videos).gastrointest Endosc 2010;72: Konda VJ, Aslanian HR, Wallace MB, Siddiqui UD, Hart J, Waxman I. First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos). Gastrointest Endosc 2011;74: S38 62 nd Congress of the Korean Society of Gastrointestinal Endoscopy Clin Endosc Vol. 45 Suppl 1, 2012