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Role of tumor markers in the diagnosis of cystic and intraductal neoplasms
Gastrointest Endoscopy Clin N Am 12 (2002) 791 – 801
Role of tumor markers in the diagnosis of cystic and intraductal neoplasms Pascal Hammel, MD, PhD Fe´de´ration Me´dico-Chirurgicale d’He´pato-Gastroente´rologie Hoˆpital Beaujon (AP-HP), 92118 Clichy Cedex, France
Despite recent advances in imaging procedures, the correct diagnosis of cystic lesions of the pancreas is lacking in about one third of cases. Cyst fluid analysis can help in the differential diagnosis, particularly in unilocular ones, thus precluding unjustified resection in patients with benign cystic lesions of the pancreas. This review deals largely with the value of cyst fluid analysis in the differential diagnosis of cystic lesions of the pancreas but it is indispensable to integrate such data with those of imaging and serum markers analysis. Most cystic lesions of the pancreas are pseudocysts. Serous cystadenomas, mucinous cystadenomas, and mucinous cystadenocarcinomas account for about 10% of pancreatic cystic tumors [1]. Solitary or multiple congenital cysts, papillary cystic tumors, cystic-ductal adenocarcinomas, and cystic endocrine tumors are less frequent [1]. Finally, intraductal papillary mucinous tumors (IMPT) of the pancreas are an increasingly recognized cystic tumor of the pancreas [2]. After discovery of a cystic lesion in the pancreatic region, three steps must be taken: (1) confirm that the lesion is really intrapancreatic; (2) distinguish a pseudocyst from a cystic tumor; (3) distinguish benign cystic tumors (ie, serous cystadenomas in a macrocystic form, true congenital cyst, lymphoepithelial cyst) from malignant or potentially malignant forms (ie, mucinous cystadenomas or cystadenocarcinomas, IPMT) [3]. Some investigators propose systematic resection of all cystic tumors of the pancreas because they estimate that preoperative distinction of benign from malignant cystic tumor is unreliable [4]. Others propose conservative management strategies in patients with asymptomatic serous cystadenomas [3,5]. The benign nature of serous cystadenomas has been questioned after few documented reports of serous cystadenocarcinomas; however, the mortality rate of a pancreatic resection itself (1% – 2%) clearly exceeds the theoretic risk of malignant transformation of a serous cystadenoma [5]. Thus,
E-mail address: [email protected] (P. Hammel). 1052-5157/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 5 2 - 5 1 5 7 ( 0 2 ) 0 0 0 2 5 - 9
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increased diagnostic precision is required to distinguish benign cystic lesions from potential or frankly malignant ones.
Limits of imaging methods in the diagnosis of cystic lesions of the pancreas Imaging methods used for the diagnosis includes ultrasonography (US), CT, MRI, and endoscopic ultrasonography (EUS) [6– 10]. Difficulties in achieving a correct diagnosis for cystic pancreatic lesions depend on the type of lesion and also the experience of the investigator [10]. Most pseudocyts have a typical presentation, and imaging diagnosis is feasible, particularly when the clinical context is evocative or when imaging features of acute or chronic pancreatitis (ie, calcifications) are present. Typical serous cystadenomas are easily recognized using CT when numerous and small cystic loculations and central calcifications are present [11]. The problem is much more complex for unilocular or paucilocular lesions because radiologic features are still not sufficiently specific to make optimal decisions in all cases. Mucinous cystadenomas can be misdiagnosed as pseudocysts, particularly when chronic pancreatic features are lacking [12]. Cystadenocarcinoma can develop several years after a mucinous cystadenoma is misdiagnosed as pseudocyst and treated by cystojejunostomy [13]. Macrocystic serous cystadenomas are difficult or even impossible to distinguish on imaging from other unilocular cystic lesions, particularly mucinous cystadenomas [14 –16]. About 10% of serous cystadenomas are prominently macrocystic [5]. In contrast, mucinous cystadenomas that do not fulfill the radiologic criteria proposed by Johnson et al [17] (measuring less than 2 cm in diameter) occasionally can exhibit precocious malignant transformation. Finally, the diagnosis of rarer cystic lesions other than cystadenomas, such as cystic endocrine tumors or lymphoepithelial cysts, is often difficult due to their infrequency and the lack of typical imaging data. Overall, the diagnosis of a cystic tumor after conventional imaging procedures remains uncertain in about 20% to 30% of cases [3,10].
Serum tumor markers Serum levels of carcinoembryonic antigen (CEA) and carbohydrate 19.9 (Ca 19.9) in patients with mucinous cystic neoplasms or IPMT have been sporadically analyzed, and the results are variable [5,18]. Ca 19.9 determination seems to be more helpful than CEA for both tumor types [18]. Serum Ca 19.9 levels were not different between benign and malignant variants in a series of 18 mucinhypersecreting tumors [19]. In the series by Leborgne et al. [5], serum Ca 19.9 was above the upper normal range in 12% of patients with serous cystadenomas, 21% of those with benign mucinous cystadenomas, and 70% of those with mucinous cystadenocarcinomas. Overall, serum tumor marker measurement has a limited value in the differential diagnosis of cystic lesions of the pancreas. They are generally not
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helpful in discriminating premalignant mucinous tumors from other benign cystic lesions. Elevation of Ca 19.9 only indicates the presence of a malignant tumor, that is, mucinous cystadenocarcinoma of malignant IPMT.
Cyst fluid analysis Technical considerations In the last decade, several reports have addressed the diagnostic value of cyst fluid analysis in differentiating cystic lesions of the pancreas [20 –26]. Preoperative percutaneous aspiration of a cystic lesion is feasible in most cases. With the recent availability of fine needle aspiration under endosonographic control (EUSFNA), theoretically almost all types of lesions can be now accessed—even those measuring less than 2 cm in diameter [27]. A sufficient amount of fluid is needed for biochemical analysis. Ideally, obtaining 2 mL or more allows analysis of different tumor markers and storage of fluid for confirmative analyses in reference biochemical units when necessary; new markers can also be analyzed for research purposes. Complications of cyst fluid aspiration The first large series by Wiersema et al [27] revealed concern about a higher risk of complication after aspiration of cystic as compared to solid pancreatic tumors. These authors reported a higher rate of nonfatal complications after EUSFNA of cystic lesions: 14% compared to aspiration of solid lesions (0.5%). Our group reported a series of 322 patients who underwent EUS-FNA for 345 lesions among which 114 were pancreatic cystic type [28]. No complication was observed after FNA of solid tumors (n = 134) but 3 cases (3.5%) of mild acute pancreatitis occurred in cystic lesions. Lesions in the head of the pancreas and especially the uncinate process are perhaps at greater risk as they are situated farther away from the EUS probe; the needle must therefore pass through a greater amount of normal pancreatic tissue before arriving at the target, thus increasing the amount of normal tissue damage. A significant risk of superinfection after aspiration of cystic lesions had been reported by Wiersema et al [27]. Our series did not confirm this, and only a randomized prospective study may address the need for antibiotic prophylaxis after EUS-FNA of pancreatic cystic lesions [28]. The theoretic risk of tumor cell seeding has not been widely examined, but it is probably very low [24].
Cytology Cytologic and histologic studies should be performed whenever possible; however, accuracy of this analysis does not exceed 40% to 75% for mucinous
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cystadenomas or cystadenocarcinomas and 10% to 25% for serous cystadenomas due to the usual paucicellularity of these lesions [5,18,22,29 –32]. Tumors markers in cyst fluid of pseudocyts and cystadenomas Several tumor markers have been tested for this purpose. CEA, Ca 19.9, and tumor-associated glycoprotein 72 (TAG-72 or CA 72.4) are the markers that have been the more widely examined [18,20,22 – 26]. CEA CEA has been shown to be a useful marker for differentiating mucinous tumors from nonmucinous ones [22 – 26]. Tatsuta et al [20] found a median value of 3 ng/mL in a series of 8 pseudocysts, and Lewandrowski et al [23] reported a lower CEA mean value in 7 pseudocyts (7.5 ng/mL) and 5 serous cystadenomas (1.1 ng/mL) than in 4 mucinous cystadenomas (7288 ng/mL) and 7 mucinous cystadenocarcinomas (22,239 ng/mL) with no overlap between mucinous and nonmucinous tumors. Pinto and Meriano [22] reported a low median value of CEA (3.2 ng/mL) in a series of 16 pseudocysts but a high content (231 ng/mL) in 1. In the series by Leborgne et al [5], CEA values of less than 5 ng/mL were present in all 9 serous cystadenomas but in only 1 of the 14 mucinous cystadenomas and none of the 4 cystadenocarcinomas. In our first report of 50 cystic lesions analyzed for this purpose (7 serous cystadenomas, 12 mucinous tumors, and 30 pseudocyts), a CEA level of < 5 ng/mL had a 100% sensitivity and a 86% specificity for the diagnosis of serous cystadenoma [24]. After additional analysis of 24 serous cystadenomas, the accuracy of this marker remained excellent for this purpose (unpublished data, Table 1). CEA level of > 400 ng/mL had a 50% sensitivity and a 100% specificity for the diagnosis of benign or malignant mucinous cystadenoma, respectively [24]. This result has been confirmed after further study of 36 mucinous tumors (unpublished data, Table 1). Table 1 Reassessment of cyst fluid biochemical and tumor markers value in the diagnosis of 130 cystic lesions of the pancreas (serous cystadenomas: n = 24, mucinous cystadenomas and cystadenocarcinomas: n = 36, pseudocysts: n = 70) studied at the Beaujon Hospital Marker Amylase Ca 19.9 CEA CEA Ca 72.4 Mucins M1
Cut-off Valuea > 5000 U/L >50 000 U/mL >400 ng/mL < 5 ng/mL >40 U/mL >1200 U/mL
Diagnosis PC MC/MCAC MC/MCAC SC MC/MCAC MC/MCAC
Sensitivity b
93 72 57 92 73 41
(94) (75) (50) (100) (63) (30)
Specificity
PPV
NPV
82 84 99 87 99 93
86 63 96 61 96 71
91 88 85 98 84 79
(74) (90) (100) (86) (98) (100)
(85) (67) (100) (54) (95) (100)
(88) (90) (85) (100) (85) (79)
Abbreviations: MC, mucinous cystadenoma; MCAC, mucinous cystadenocarcinoma; NPV, negative predictive value; PC, pseudocyst; PPV, predictive positive value; SC, serous cystadenoma. Values in parentheses were previously published by our group (see references [24,34,37]). a Cut-off values b Diagnostic accuracy of the markers (numbers are percentages).
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Ca 19.9 Intracystic Ca 19.9 is a less discriminating marker in the diagnosis of such tumors. Several investigators reported a variable and frequently overlapping range of Ca 19.9 values in various benign and malignant cystic tumors of the pancreas and concluded that this marker was not sufficiently discriminative [24 – 26]. In our first series [24], only a level >50,000 U/mL provided an acceptable accuracy in the diagnosis of mucinous tumors. Using this cutoff value, sensitivity and specificity were 75% and 90%, respectively. Recent reassessment of this marker with the same cutoff after analysis of 130 cystic lesions indicated a 72% sensitivity and an 84% specificity (unpublished data, Table 1). It is important to stress that pseudocysts and even serous cystadenomas may contain high levels of Ca 19.9. We have hypothesized that fibrosis and hemorrhage are occasionally found surrounding serous cystadenomas, which may lead to contamination of cyst fluid by pancreatic juice containing high level of Ca 19.9 [24]. CA 72.4 CA 72.4 is one of the best markers in differentiating mucinous cystic tumors from nonmucinous tumors. Alles et al [33] found a clear difference between low CA 72.4 values encountered in fluid of both serous cystadenomas (all < 3 U/mL) and pseudocysts (median 5.7, range < 3– 5.7 U/mL) and the high values found in mucinous cystadenomas (median 39.9, range 4.3– 137.1 U/mL) and cystadenocarcinomas (median 4063, range 780– 34,853 U/mL). They also noticed that the CA 72.4 fluid content in mucinous cystadenocarcinomas was higher than in benign mucinous cystadenomas [33]. After analysis of 91 lesions (16 serous cystadenomas, 16 mucinous cystadenomas, 14 cystadenocarcinomas, and 45 pseudocysts), we found that a CA 72.4 level of > 40 U/mL had a 63% sensitivity and a 98% specificity for distinguishing mucinous tumors from pseudocyst and serous cystadenomas [34]. CA 72.4 values of cystadenocarcinomas were higher compared to that of benign mucinous cystadenomas (median 210, range 3 – 8000 U/mL versus median 15, range 1– 1000 U/mL, P < 0.05); however, overlap of values was nonetheless frequent. In addition, the preoperative distinction between these two forms of cystadenomas is of limited practical interest as they are both generally resected [12]. Our recent reassessment of this marker confirmed its diagnostic value (unpublished data, Table 1). CA 15.3 CA 15.3 is a mucin glycoprotein antigen present in human milk-fat globule membrane. Rubin et al [35] have shown that high content of this marker in cyst fluid of pancreatic cystic lesions tended to indicate malignant transformation. In their series, CA 15.3 content was higher in mucinous cystadenocarcinomas compared to benign mucinous cystadenomas, serous cystadenomas, or pseudocyts. An upper cutoff value of 30 U/mL distinguished mucinous cystic neoplasms from mucinous cystadenocarcinomas with 100% sensitivity and 100% specificity [35]. Sperti et al [36] have confirmed the limited sensitivity (50%) but the high
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specificity (94%) of this marker for the diagnosis of mucinous cystic tumors of the pancreas. Mucins The analysis of mucins content in cystic lesions of the pancreas is appealing. Lewandrowski et al [25] demonstrated that high viscosity of cyst content measured either preoperatively or perioperatively was useful in indicating the mucinous nature of a cystic tumor [25]. This analysis, however, is not routinely performed and some mucinous cystadenomas can exhibit low viscosity, possibly because of mucins destruction by pancreatic enzymes. In a series of 14 cystadenomas and 10 pseudocysts, Sperti et al [36] reported that a high mucinlike carcinoma-associated antigen (MCA) content was higher in mucinous cystadenomas than in serous cystadenomas or in pseudocysts. This marker was elevated in seven of eight mucinous tumors. In addition, MCA level was higher in mucinous cystadenocarcinomas (133.7 U/mL) than in benign cystadenomas (37.5 U/mL). The sensitivity of Ca 15.3, CEA, and CA 72.4 in detecting mucinous neoplasm was 50%, 87.5%, and 87.5%, with a specificity of 94%, 44%, and 94%, respectively. In a study published in 1997, we reported the analysis of gastric mucins M1 antigen in a series of 65 cystic lesions of the pancreas (12 serous cystadenomas, 9 mucinous cystadenomas, 8 cystadenocarcinomas, and 6 IPMT)[37]. Mucin value greater than 50 UM1/mL provided a 78% sensitivity and a 100% specificity in distinguishing mucinous tumors from serous cystadenomas; however, only a value greater than 1200 U M1/mL allowed discrimination between mucinous tumors and pseudocyts with a 30% sensitivity and a 100% specificity [37]. Interestingly, use of CEA and M1 mucin antigen analysis in combination improved the diagnostic accuracy for mucinous tumors (sensitivity, 60%, specificity, 100%). Extending this analysis to a greater number of lesions, we have become concerned not only for pseudocysts but also in relation to several serous cystadenomas that contained high levels of M1 mucin antigen (unpublished data, Table 1). The reason for this observation remains unexplained and their routine use cannot at this stage be recommended. Other tumor markers The interest of K-ras mutation detection in cystic tumors of the pancreas has been examined to a limited extent. Tateishi et al [38] found a 43% rate of K-ras mutations in 14 cystic lesions after performing pancreatic juice analysis. The mutation was absent in the serous cystadenoma studied, but present in two mucinous cystadenomas. Using direct analysis of cyst fluid, our previous data suggested that presence of K-ras mutation was helpful in distinguishing mucinous cystadenocarcinomas from other cystic lesions of the pancreas [39]. Knowing that about 15% patients with chronic pancreatitis exhibit K-ras mutation in pancreatic juice, however, the accuracy of this marker in differentiating pseudocyst from mucinous tumors remains questionable. Extension of role of K-ras mutation analysis in prospective studies merits further attention.
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Several other tumor markers (CA 125, elastase-1, proliferative tissue peptide antigen) or inflammatory markers (pancreatic associated protein, PS2 protein, TGFa, etc) also have been analyzed [18,20,26,40]. Despite interesting results for certain markers examined, the number of patients studied is too small to draw conclusions.
Tumor markers analysis in cyst fluid of other cystic lesions of the pancreas Consistent data about cyst fluid analysis in pancreatic cystic lesions are only available for cystadenomas and pseudocysts. Data concerning IPMT cyst fluid contents are scare. Yamaguchi et al [19] reported in a series of 18 IPMTs that serum and fluid analysis of tumor markers was of limited diagnostic value. In our experience, these lesions may exhibit variable levels of tumor markers in cyst fluid [37]. We have largely determined two biochemical profiles: in some lesions, the profile is similar to that of mucinous cystadenomas or cystadenocarcinomas with high levels of CEA, Ca 19.9, and CA 72.4 (unpublished data); in other lesions, tumor markers are intermediate and pancreatic enzymes are high, with a cyst fluid biochemical profile resembling that of pseudocyts. The latter could be explained by the mixture of fluids between IPMT lesions, which communicate with pancreatic ducts of the unaffected pancreas. In contrast, cystadenomas usually do not communicate with pancreatic ducts and, thus, tumor markers accumulate in the fluid of such lesions. Z’graggen et al [41] have shown that the rate of K-ras mutations in various histologic specimens of IPMT correlated with the stage of neoplastic evolution to cancer, ranging from 16.7% in normal epithelium and papillary hyperplasia to 57.1% in high-grade dysplasia and invasive carcinoma. Thus, cystic fluid K-ras mutation detection appears not to be helpful in diagnosing IPMT at an early (benign) stage. Other rare cystic tumors have also been poorly studied. True cysts of the pancreas, either isolated or in multiple forms as observed in patients with the von Hippel-Lindau disease, contain low concentrations of tumor markers similar to serous cystadenoma [42]. A case of a pseudosolid and papillary tumor with low cyst fluid content of tumor markers has been reported [43]. Peripancreatic cystic lesion, such as mesenteric of lymphoepithelial cysts or intestinal duplications, may contain high concentrations of tumor markers [44]. Benign liver cysts contain high concentrations of Ca 19.9 [45]. Overall, when confronted with rare tumors, the use of tumor marker analysis should be interpreted with caution as insufficient experience has been accrued.
Indications for tumor markers assessment in cyst fluid Performing analysis of fluid contents of a cystic lesion of the pancreas requires rigorous patient selection. Schematically, three situations can be isolated: (1) The lesion consists of a unilocular or paucilocular macrocyst on imaging in the absence
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of a context of acute or chronic pancreatitis. The most likely diagnosis is of a mucinous cystadenoma (benign or dysplasic), but a macrocystic serous cystadenoma or a congenital cyst cannot be excluded. Although EUS or MRI may be helpful, there is clearly an indication for cyst fluid analysis. This tool may help ascertain the diagnosis, showing high content of tumor markers. In contrast, low levels of tumor markers indicate a benign lesion such as a macrocystic serous cystadenoma or a congenital cyst. Cyst fluid tumor markers thus help in proposing management strategies with greater certainty. (2) The diagnosis of malignant cystic tumor (ie, cystadenocarcinoma of pseudopapillary tumor) is highly suspected on imaging as the lesion contains solids components or vegetations and is limited by a thick, nodular, or irregular wall. FNA of intracystic fluid is not indicated and surgical resection is required. If the lesion is unresectable because of locoregional tumor extension, EUS-FNA biopsy of tumor tissue can help to assess malignancy and palliative treatment can be envisaged. (3) In cases of atypical serous cystadenoma (ie, prominently macrocystic) or atypical mucinous cystadenoma (ie, size < 2 cm) at imaging, analysis of cyst fluid can provide additional diagnostic arguments before proposing management strategies.
Summary Despite recent advances in imaging procedures, the correct diagnosis of cystic lesions of the pancreas is lacking in about one third of cases. Cyst fluid analysis can help in the differential diagnosis, particularly in patients with unilocular or paucilocular lesions, thus precluding unjustified resection in patients with benign cystic lesions of the pancreas. Although use of cystic fluid marker analysis is helpful in several situations, it is crucial to carefully evaluate the clinical context with appraisal of patient’s demographics, clinical symptoms, and morphologic data. A multidisciplinary approach is advised and should improve the overall diagnostic performance and lead to better management strategies in patients presenting with such tumors of the pancreas.
Acknowledgments The author thanks all members of our group at Beaujon hospital who participate in the management of patients with pancreatic diseases: Prs. Ph. Ruszniewski and P. Le´vy, Dr. O’Toole and F. Maire, Drs. L. Palazzo, A. Dancour, and A. Aubert (endoscopic ultrasonography and fine-needle aspiration), Dr. Ph. Ponsot (ERCP), Pr. V. Vilgrain, and Dr. MP Vuillerme (Imaging), Dr. H. Voitot (Biochemistry), Dr. A. Couvelard (Pathology), Prs. J. Belghiti, A. Sauvanet, and O. Farges, and Dr. R. Kianmanesh (Surgery). Special thanks to Dr. Dermot O’Toole for his help in the preparation of the manuscript.
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Role of tumor markers in the diagnosis of cystic and intraductal neoplasms Pascal Hammel, MD, PhD Fe´de´ration Me´dico-Chirurgicale d’He´pato-Gastroente´rologie Hoˆpital Beaujon (AP-HP), 92118 Clichy Cedex, France
Despite recent advances in imaging procedures, the correct diagnosis of cystic lesions of the pancreas is lacking in about one third of cases. Cyst fluid analysis can help in the differential diagnosis, particularly in unilocular ones, thus precluding unjustified resection in patients with benign cystic lesions of the pancreas. This review deals largely with the value of cyst fluid analysis in the differential diagnosis of cystic lesions of the pancreas but it is indispensable to integrate such data with those of imaging and serum markers analysis. Most cystic lesions of the pancreas are pseudocysts. Serous cystadenomas, mucinous cystadenomas, and mucinous cystadenocarcinomas account for about 10% of pancreatic cystic tumors [1]. Solitary or multiple congenital cysts, papillary cystic tumors, cystic-ductal adenocarcinomas, and cystic endocrine tumors are less frequent [1]. Finally, intraductal papillary mucinous tumors (IMPT) of the pancreas are an increasingly recognized cystic tumor of the pancreas [2]. After discovery of a cystic lesion in the pancreatic region, three steps must be taken: (1) confirm that the lesion is really intrapancreatic; (2) distinguish a pseudocyst from a cystic tumor; (3) distinguish benign cystic tumors (ie, serous cystadenomas in a macrocystic form, true congenital cyst, lymphoepithelial cyst) from malignant or potentially malignant forms (ie, mucinous cystadenomas or cystadenocarcinomas, IPMT) [3]. Some investigators propose systematic resection of all cystic tumors of the pancreas because they estimate that preoperative distinction of benign from malignant cystic tumor is unreliable [4]. Others propose conservative management strategies in patients with asymptomatic serous cystadenomas [3,5]. The benign nature of serous cystadenomas has been questioned after few documented reports of serous cystadenocarcinomas; however, the mortality rate of a pancreatic resection itself (1% – 2%) clearly exceeds the theoretic risk of malignant transformation of a serous cystadenoma [5]. Thus,
E-mail address: [email protected] (P. Hammel). 1052-5157/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 5 2 - 5 1 5 7 ( 0 2 ) 0 0 0 2 5 - 9
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increased diagnostic precision is required to distinguish benign cystic lesions from potential or frankly malignant ones.
Limits of imaging methods in the diagnosis of cystic lesions of the pancreas Imaging methods used for the diagnosis includes ultrasonography (US), CT, MRI, and endoscopic ultrasonography (EUS) [6– 10]. Difficulties in achieving a correct diagnosis for cystic pancreatic lesions depend on the type of lesion and also the experience of the investigator [10]. Most pseudocyts have a typical presentation, and imaging diagnosis is feasible, particularly when the clinical context is evocative or when imaging features of acute or chronic pancreatitis (ie, calcifications) are present. Typical serous cystadenomas are easily recognized using CT when numerous and small cystic loculations and central calcifications are present [11]. The problem is much more complex for unilocular or paucilocular lesions because radiologic features are still not sufficiently specific to make optimal decisions in all cases. Mucinous cystadenomas can be misdiagnosed as pseudocysts, particularly when chronic pancreatic features are lacking [12]. Cystadenocarcinoma can develop several years after a mucinous cystadenoma is misdiagnosed as pseudocyst and treated by cystojejunostomy [13]. Macrocystic serous cystadenomas are difficult or even impossible to distinguish on imaging from other unilocular cystic lesions, particularly mucinous cystadenomas [14 –16]. About 10% of serous cystadenomas are prominently macrocystic [5]. In contrast, mucinous cystadenomas that do not fulfill the radiologic criteria proposed by Johnson et al [17] (measuring less than 2 cm in diameter) occasionally can exhibit precocious malignant transformation. Finally, the diagnosis of rarer cystic lesions other than cystadenomas, such as cystic endocrine tumors or lymphoepithelial cysts, is often difficult due to their infrequency and the lack of typical imaging data. Overall, the diagnosis of a cystic tumor after conventional imaging procedures remains uncertain in about 20% to 30% of cases [3,10].
Serum tumor markers Serum levels of carcinoembryonic antigen (CEA) and carbohydrate 19.9 (Ca 19.9) in patients with mucinous cystic neoplasms or IPMT have been sporadically analyzed, and the results are variable [5,18]. Ca 19.9 determination seems to be more helpful than CEA for both tumor types [18]. Serum Ca 19.9 levels were not different between benign and malignant variants in a series of 18 mucinhypersecreting tumors [19]. In the series by Leborgne et al. [5], serum Ca 19.9 was above the upper normal range in 12% of patients with serous cystadenomas, 21% of those with benign mucinous cystadenomas, and 70% of those with mucinous cystadenocarcinomas. Overall, serum tumor marker measurement has a limited value in the differential diagnosis of cystic lesions of the pancreas. They are generally not
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helpful in discriminating premalignant mucinous tumors from other benign cystic lesions. Elevation of Ca 19.9 only indicates the presence of a malignant tumor, that is, mucinous cystadenocarcinoma of malignant IPMT.
Cyst fluid analysis Technical considerations In the last decade, several reports have addressed the diagnostic value of cyst fluid analysis in differentiating cystic lesions of the pancreas [20 –26]. Preoperative percutaneous aspiration of a cystic lesion is feasible in most cases. With the recent availability of fine needle aspiration under endosonographic control (EUSFNA), theoretically almost all types of lesions can be now accessed—even those measuring less than 2 cm in diameter [27]. A sufficient amount of fluid is needed for biochemical analysis. Ideally, obtaining 2 mL or more allows analysis of different tumor markers and storage of fluid for confirmative analyses in reference biochemical units when necessary; new markers can also be analyzed for research purposes. Complications of cyst fluid aspiration The first large series by Wiersema et al [27] revealed concern about a higher risk of complication after aspiration of cystic as compared to solid pancreatic tumors. These authors reported a higher rate of nonfatal complications after EUSFNA of cystic lesions: 14% compared to aspiration of solid lesions (0.5%). Our group reported a series of 322 patients who underwent EUS-FNA for 345 lesions among which 114 were pancreatic cystic type [28]. No complication was observed after FNA of solid tumors (n = 134) but 3 cases (3.5%) of mild acute pancreatitis occurred in cystic lesions. Lesions in the head of the pancreas and especially the uncinate process are perhaps at greater risk as they are situated farther away from the EUS probe; the needle must therefore pass through a greater amount of normal pancreatic tissue before arriving at the target, thus increasing the amount of normal tissue damage. A significant risk of superinfection after aspiration of cystic lesions had been reported by Wiersema et al [27]. Our series did not confirm this, and only a randomized prospective study may address the need for antibiotic prophylaxis after EUS-FNA of pancreatic cystic lesions [28]. The theoretic risk of tumor cell seeding has not been widely examined, but it is probably very low [24].
Cytology Cytologic and histologic studies should be performed whenever possible; however, accuracy of this analysis does not exceed 40% to 75% for mucinous
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cystadenomas or cystadenocarcinomas and 10% to 25% for serous cystadenomas due to the usual paucicellularity of these lesions [5,18,22,29 –32]. Tumors markers in cyst fluid of pseudocyts and cystadenomas Several tumor markers have been tested for this purpose. CEA, Ca 19.9, and tumor-associated glycoprotein 72 (TAG-72 or CA 72.4) are the markers that have been the more widely examined [18,20,22 – 26]. CEA CEA has been shown to be a useful marker for differentiating mucinous tumors from nonmucinous ones [22 – 26]. Tatsuta et al [20] found a median value of 3 ng/mL in a series of 8 pseudocysts, and Lewandrowski et al [23] reported a lower CEA mean value in 7 pseudocyts (7.5 ng/mL) and 5 serous cystadenomas (1.1 ng/mL) than in 4 mucinous cystadenomas (7288 ng/mL) and 7 mucinous cystadenocarcinomas (22,239 ng/mL) with no overlap between mucinous and nonmucinous tumors. Pinto and Meriano [22] reported a low median value of CEA (3.2 ng/mL) in a series of 16 pseudocysts but a high content (231 ng/mL) in 1. In the series by Leborgne et al [5], CEA values of less than 5 ng/mL were present in all 9 serous cystadenomas but in only 1 of the 14 mucinous cystadenomas and none of the 4 cystadenocarcinomas. In our first report of 50 cystic lesions analyzed for this purpose (7 serous cystadenomas, 12 mucinous tumors, and 30 pseudocyts), a CEA level of < 5 ng/mL had a 100% sensitivity and a 86% specificity for the diagnosis of serous cystadenoma [24]. After additional analysis of 24 serous cystadenomas, the accuracy of this marker remained excellent for this purpose (unpublished data, Table 1). CEA level of > 400 ng/mL had a 50% sensitivity and a 100% specificity for the diagnosis of benign or malignant mucinous cystadenoma, respectively [24]. This result has been confirmed after further study of 36 mucinous tumors (unpublished data, Table 1). Table 1 Reassessment of cyst fluid biochemical and tumor markers value in the diagnosis of 130 cystic lesions of the pancreas (serous cystadenomas: n = 24, mucinous cystadenomas and cystadenocarcinomas: n = 36, pseudocysts: n = 70) studied at the Beaujon Hospital Marker Amylase Ca 19.9 CEA CEA Ca 72.4 Mucins M1
Cut-off Valuea > 5000 U/L >50 000 U/mL >400 ng/mL < 5 ng/mL >40 U/mL >1200 U/mL
Diagnosis PC MC/MCAC MC/MCAC SC MC/MCAC MC/MCAC
Sensitivity b
93 72 57 92 73 41
(94) (75) (50) (100) (63) (30)
Specificity
PPV
NPV
82 84 99 87 99 93
86 63 96 61 96 71
91 88 85 98 84 79
(74) (90) (100) (86) (98) (100)
(85) (67) (100) (54) (95) (100)
(88) (90) (85) (100) (85) (79)
Abbreviations: MC, mucinous cystadenoma; MCAC, mucinous cystadenocarcinoma; NPV, negative predictive value; PC, pseudocyst; PPV, predictive positive value; SC, serous cystadenoma. Values in parentheses were previously published by our group (see references [24,34,37]). a Cut-off values b Diagnostic accuracy of the markers (numbers are percentages).
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Ca 19.9 Intracystic Ca 19.9 is a less discriminating marker in the diagnosis of such tumors. Several investigators reported a variable and frequently overlapping range of Ca 19.9 values in various benign and malignant cystic tumors of the pancreas and concluded that this marker was not sufficiently discriminative [24 – 26]. In our first series [24], only a level >50,000 U/mL provided an acceptable accuracy in the diagnosis of mucinous tumors. Using this cutoff value, sensitivity and specificity were 75% and 90%, respectively. Recent reassessment of this marker with the same cutoff after analysis of 130 cystic lesions indicated a 72% sensitivity and an 84% specificity (unpublished data, Table 1). It is important to stress that pseudocysts and even serous cystadenomas may contain high levels of Ca 19.9. We have hypothesized that fibrosis and hemorrhage are occasionally found surrounding serous cystadenomas, which may lead to contamination of cyst fluid by pancreatic juice containing high level of Ca 19.9 [24]. CA 72.4 CA 72.4 is one of the best markers in differentiating mucinous cystic tumors from nonmucinous tumors. Alles et al [33] found a clear difference between low CA 72.4 values encountered in fluid of both serous cystadenomas (all < 3 U/mL) and pseudocysts (median 5.7, range < 3– 5.7 U/mL) and the high values found in mucinous cystadenomas (median 39.9, range 4.3– 137.1 U/mL) and cystadenocarcinomas (median 4063, range 780– 34,853 U/mL). They also noticed that the CA 72.4 fluid content in mucinous cystadenocarcinomas was higher than in benign mucinous cystadenomas [33]. After analysis of 91 lesions (16 serous cystadenomas, 16 mucinous cystadenomas, 14 cystadenocarcinomas, and 45 pseudocysts), we found that a CA 72.4 level of > 40 U/mL had a 63% sensitivity and a 98% specificity for distinguishing mucinous tumors from pseudocyst and serous cystadenomas [34]. CA 72.4 values of cystadenocarcinomas were higher compared to that of benign mucinous cystadenomas (median 210, range 3 – 8000 U/mL versus median 15, range 1– 1000 U/mL, P < 0.05); however, overlap of values was nonetheless frequent. In addition, the preoperative distinction between these two forms of cystadenomas is of limited practical interest as they are both generally resected [12]. Our recent reassessment of this marker confirmed its diagnostic value (unpublished data, Table 1). CA 15.3 CA 15.3 is a mucin glycoprotein antigen present in human milk-fat globule membrane. Rubin et al [35] have shown that high content of this marker in cyst fluid of pancreatic cystic lesions tended to indicate malignant transformation. In their series, CA 15.3 content was higher in mucinous cystadenocarcinomas compared to benign mucinous cystadenomas, serous cystadenomas, or pseudocyts. An upper cutoff value of 30 U/mL distinguished mucinous cystic neoplasms from mucinous cystadenocarcinomas with 100% sensitivity and 100% specificity [35]. Sperti et al [36] have confirmed the limited sensitivity (50%) but the high
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specificity (94%) of this marker for the diagnosis of mucinous cystic tumors of the pancreas. Mucins The analysis of mucins content in cystic lesions of the pancreas is appealing. Lewandrowski et al [25] demonstrated that high viscosity of cyst content measured either preoperatively or perioperatively was useful in indicating the mucinous nature of a cystic tumor [25]. This analysis, however, is not routinely performed and some mucinous cystadenomas can exhibit low viscosity, possibly because of mucins destruction by pancreatic enzymes. In a series of 14 cystadenomas and 10 pseudocysts, Sperti et al [36] reported that a high mucinlike carcinoma-associated antigen (MCA) content was higher in mucinous cystadenomas than in serous cystadenomas or in pseudocysts. This marker was elevated in seven of eight mucinous tumors. In addition, MCA level was higher in mucinous cystadenocarcinomas (133.7 U/mL) than in benign cystadenomas (37.5 U/mL). The sensitivity of Ca 15.3, CEA, and CA 72.4 in detecting mucinous neoplasm was 50%, 87.5%, and 87.5%, with a specificity of 94%, 44%, and 94%, respectively. In a study published in 1997, we reported the analysis of gastric mucins M1 antigen in a series of 65 cystic lesions of the pancreas (12 serous cystadenomas, 9 mucinous cystadenomas, 8 cystadenocarcinomas, and 6 IPMT)[37]. Mucin value greater than 50 UM1/mL provided a 78% sensitivity and a 100% specificity in distinguishing mucinous tumors from serous cystadenomas; however, only a value greater than 1200 U M1/mL allowed discrimination between mucinous tumors and pseudocyts with a 30% sensitivity and a 100% specificity [37]. Interestingly, use of CEA and M1 mucin antigen analysis in combination improved the diagnostic accuracy for mucinous tumors (sensitivity, 60%, specificity, 100%). Extending this analysis to a greater number of lesions, we have become concerned not only for pseudocysts but also in relation to several serous cystadenomas that contained high levels of M1 mucin antigen (unpublished data, Table 1). The reason for this observation remains unexplained and their routine use cannot at this stage be recommended. Other tumor markers The interest of K-ras mutation detection in cystic tumors of the pancreas has been examined to a limited extent. Tateishi et al [38] found a 43% rate of K-ras mutations in 14 cystic lesions after performing pancreatic juice analysis. The mutation was absent in the serous cystadenoma studied, but present in two mucinous cystadenomas. Using direct analysis of cyst fluid, our previous data suggested that presence of K-ras mutation was helpful in distinguishing mucinous cystadenocarcinomas from other cystic lesions of the pancreas [39]. Knowing that about 15% patients with chronic pancreatitis exhibit K-ras mutation in pancreatic juice, however, the accuracy of this marker in differentiating pseudocyst from mucinous tumors remains questionable. Extension of role of K-ras mutation analysis in prospective studies merits further attention.
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Several other tumor markers (CA 125, elastase-1, proliferative tissue peptide antigen) or inflammatory markers (pancreatic associated protein, PS2 protein, TGFa, etc) also have been analyzed [18,20,26,40]. Despite interesting results for certain markers examined, the number of patients studied is too small to draw conclusions.
Tumor markers analysis in cyst fluid of other cystic lesions of the pancreas Consistent data about cyst fluid analysis in pancreatic cystic lesions are only available for cystadenomas and pseudocysts. Data concerning IPMT cyst fluid contents are scare. Yamaguchi et al [19] reported in a series of 18 IPMTs that serum and fluid analysis of tumor markers was of limited diagnostic value. In our experience, these lesions may exhibit variable levels of tumor markers in cyst fluid [37]. We have largely determined two biochemical profiles: in some lesions, the profile is similar to that of mucinous cystadenomas or cystadenocarcinomas with high levels of CEA, Ca 19.9, and CA 72.4 (unpublished data); in other lesions, tumor markers are intermediate and pancreatic enzymes are high, with a cyst fluid biochemical profile resembling that of pseudocyts. The latter could be explained by the mixture of fluids between IPMT lesions, which communicate with pancreatic ducts of the unaffected pancreas. In contrast, cystadenomas usually do not communicate with pancreatic ducts and, thus, tumor markers accumulate in the fluid of such lesions. Z’graggen et al [41] have shown that the rate of K-ras mutations in various histologic specimens of IPMT correlated with the stage of neoplastic evolution to cancer, ranging from 16.7% in normal epithelium and papillary hyperplasia to 57.1% in high-grade dysplasia and invasive carcinoma. Thus, cystic fluid K-ras mutation detection appears not to be helpful in diagnosing IPMT at an early (benign) stage. Other rare cystic tumors have also been poorly studied. True cysts of the pancreas, either isolated or in multiple forms as observed in patients with the von Hippel-Lindau disease, contain low concentrations of tumor markers similar to serous cystadenoma [42]. A case of a pseudosolid and papillary tumor with low cyst fluid content of tumor markers has been reported [43]. Peripancreatic cystic lesion, such as mesenteric of lymphoepithelial cysts or intestinal duplications, may contain high concentrations of tumor markers [44]. Benign liver cysts contain high concentrations of Ca 19.9 [45]. Overall, when confronted with rare tumors, the use of tumor marker analysis should be interpreted with caution as insufficient experience has been accrued.
Indications for tumor markers assessment in cyst fluid Performing analysis of fluid contents of a cystic lesion of the pancreas requires rigorous patient selection. Schematically, three situations can be isolated: (1) The lesion consists of a unilocular or paucilocular macrocyst on imaging in the absence
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of a context of acute or chronic pancreatitis. The most likely diagnosis is of a mucinous cystadenoma (benign or dysplasic), but a macrocystic serous cystadenoma or a congenital cyst cannot be excluded. Although EUS or MRI may be helpful, there is clearly an indication for cyst fluid analysis. This tool may help ascertain the diagnosis, showing high content of tumor markers. In contrast, low levels of tumor markers indicate a benign lesion such as a macrocystic serous cystadenoma or a congenital cyst. Cyst fluid tumor markers thus help in proposing management strategies with greater certainty. (2) The diagnosis of malignant cystic tumor (ie, cystadenocarcinoma of pseudopapillary tumor) is highly suspected on imaging as the lesion contains solids components or vegetations and is limited by a thick, nodular, or irregular wall. FNA of intracystic fluid is not indicated and surgical resection is required. If the lesion is unresectable because of locoregional tumor extension, EUS-FNA biopsy of tumor tissue can help to assess malignancy and palliative treatment can be envisaged. (3) In cases of atypical serous cystadenoma (ie, prominently macrocystic) or atypical mucinous cystadenoma (ie, size < 2 cm) at imaging, analysis of cyst fluid can provide additional diagnostic arguments before proposing management strategies.
Summary Despite recent advances in imaging procedures, the correct diagnosis of cystic lesions of the pancreas is lacking in about one third of cases. Cyst fluid analysis can help in the differential diagnosis, particularly in patients with unilocular or paucilocular lesions, thus precluding unjustified resection in patients with benign cystic lesions of the pancreas. Although use of cystic fluid marker analysis is helpful in several situations, it is crucial to carefully evaluate the clinical context with appraisal of patient’s demographics, clinical symptoms, and morphologic data. A multidisciplinary approach is advised and should improve the overall diagnostic performance and lead to better management strategies in patients presenting with such tumors of the pancreas.
Acknowledgments The author thanks all members of our group at Beaujon hospital who participate in the management of patients with pancreatic diseases: Prs. Ph. Ruszniewski and P. Le´vy, Dr. O’Toole and F. Maire, Drs. L. Palazzo, A. Dancour, and A. Aubert (endoscopic ultrasonography and fine-needle aspiration), Dr. Ph. Ponsot (ERCP), Pr. V. Vilgrain, and Dr. MP Vuillerme (Imaging), Dr. H. Voitot (Biochemistry), Dr. A. Couvelard (Pathology), Prs. J. Belghiti, A. Sauvanet, and O. Farges, and Dr. R. Kianmanesh (Surgery). Special thanks to Dr. Dermot O’Toole for his help in the preparation of the manuscript.
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