Eur Surg Res 2015;55:352–363 DOI: 10.1159/000441492 Received: June 1, 2015 Accepted after revision: October 6, 2015 Published online: October 28, 2015

© 2015 S. Karger AG, Basel 0014–312X/15/0554–0352$39.50/0 www.karger.com/esr

Invited Review

Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas Julia Benzel

Volker Fendrich

Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany

Key Words Intraductal papillary mucinous neoplasms · Methylation · miRNA · Oncogenes · Tumor suppressor genes Abstract Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are noninvasive neoplasms which occur in the main pancreatic duct or its major branches. IPMNs have an important meaning in the clinic and in research since they represent around 20% of all resected pancreatic neoplasms. Morphologically, branch duct, main duct and mixed-type IPMNs can be distinguished. Histologically, they can be divided into gastric, intestinal, pancreatobiliary and oncocytic type. There are different mutations in genes such as KRAS, GNAS, RNF43 and p53. The expression of miRNAs is specific to IPMNs; altogether, 14 miRNAs have been identified so far which are differently expressed in all IPMNs in contrast to normal pancreatic tissue. It has also been observed that methylation levels can be altered in IPMNs. This review summarizes the molecular characteristics of IPMNs of the pancreas and presents currently known markers. © 2015 S. Karger AG, Basel

Introduction

Volker Fendrich, MD Department of Visceral, Thoracic and Vascular Surgery Philipps University Marburg, Baldinger Strasse DE–35033 Marburg (Germany) E-Mail fendrich @ med.uni-marburg.de

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Intraductal papillary mucinous neoplasm (IPMN) of the pancreas was first identified in the 1980s and ascribed to the group of pancreatic mucinous cystic neoplasms (MCNs). It is described as a papillary proliferation affecting the main pancreatic duct, its major properties being severe dilation and an overproduction of mucus [1]. It belongs to the heterogeneous cystic precursor lesions of pancreatic cancer [2, 3]. IPMNs are lesions like cystic or epithelial neoplasms with ductal differentiation [4]. They display cystic dilation of the duct accom-

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Eur Surg Res 2015;55:352–363 DOI: 10.1159/000441492

© 2015 S. Karger AG, Basel www.karger.com/esr

Benzel and Fendrich: Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas

panied by neoplastic epithelial growth in the papillae (varying in grades of dysplasia and in morphology) and secretion of abundant mucin [5]. IPMNs develop from stem cells in the epithelium of large and small pancreatic ducts [3]. These neoplasms represent a broad spectrum ranging from low-grade dysplastic tumors to invasive cancer [6]. IPMNs lack the ovarian stroma characteristic of MCNs. The papillary epithelial component, the degree of secreted mucin and cystic dilatations vary. IPMNs have a malignant potential and can be precursors of invasive pancreatic ductal adenocarcinoma (PDAC) [7]. In contrast to PDAC, IPMNs present a less aggressive tumor growth, and the survival rate of patients is higher [8]. IPMNs are the most common cystic tumors, but for a long time, they have been misdiagnosed as mucinous cystadenocarcinoma, PDAC in situ or chronic pancreatitis [3]. The risk of such a false diagnosis is the mis- or overtreatment of patients. Nevertheless, the prognosis of IPMNs is poor in cases where there is an association with invasive carcinoma [9]. In contrast, pancreatic cysts alone can be harmless, including IPMNs, MCNs, solid pseudopapillary neoplasms and pseudocysts [3, 10]. Specific differences between these types of cystic lesions of the pancreas have been reviewed by Grützmann et al. [3]. If the neoplasm is resected before transformation into invasive carcinoma, the survival rate amounts to 100% [10]. However, pancreatic intraepithelial neoplasms (PanINs), IPMNs and MCNs can develop further into pancreatic cancer [11].

IPMNs occur in patients between 60 and 70 years of age; the average age at diagnosis is 62–67 years, and men are affected slightly more often than women [9, 12, 13]. If there is an association with invasive carcinoma, the diagnosis can usually be made 3–5 years earlier [9]. The symptoms of IPMNs are unspecific and not present in all cases [1]. 7–43% of the patients do not show any symptoms [3], which can be epigastric discomfort or abdominal pain (70–80%), nausea and vomiting (11–21%), weight loss (20–40%), diabetes mellitus (16–39%), jaundice (8–30%), pancreatitis (13–43%) or steatorrhea [1, 3, 13]. Main duct (MD) IPMNs mostly cause symptoms, whereas branch duct (BD) IPMNs are often asymptomatic [9]. It is necessary to predict the malignancy of IPMNs before treatment because of the different potentials of developing into a carcinoma in situ [14]. Therefore, it is important to find risk factors and markers. The body mass index can serve only as a weak evidence for cancer of the pancreas [15]. A positive smoking history correlates with MD IPMN but is not considered to be a risk factor for high-grade dysplasia or invasive carcinoma in IPMNs [16]. Patulous papilla, jaundice, diabetes mellitus, tumor size, the size of the main pancreatic duct and the serum level of carbohydrate antigen 19-9 (CA19-9, with a threshold of 35 ng/ ml) serve as important markers for the characterization of a malignant IPMN [14, 17]. CA19-9 is also a validated tumor marker in clinical use for pancreatic cancer [18]. In contrast, gender, localization, mural nodules, abdominal pain, other tumors, a history of pancreatitis, age, cyst size, serum carcinoembryonic antigen (CEA) and serum amylase do not function as reliable significant markers, which is shown by Fujino et al. [14]. Compared to serum CEA (threshold of 5 ng/ml), serum CA19-9 is a better predictor of malignancy [17]. Nevertheless, CEA as a 180-kDa cell surface glycoprotein, which is produced by the neoplastic mucinous epithelium, allows a differentiation from mucinous and serous pancreatic cysts. The distinction is possible in 80% of the cases [10, 17]. Maker et al. [19] identified different cyst fluid glycoprotein and amylase expressions in IPMNs to distinguish between the major types of cystic neoplasms. They also identified CEA as a marker to differentiate between mucinous and nonmucinous pancreatic cystic lesions with a cutoff of 192 ng/ml, a sensitivity of 73%, a specificity of 84% and an accuracy of 79%.

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Symptoms and Diagnosis

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Eur Surg Res 2015;55:352–363 DOI: 10.1159/000441492

© 2015 S. Karger AG, Basel www.karger.com/esr

Benzel and Fendrich: Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas

In addition, other markers are characteristic of IPMNs. CA19-9 has a cutoff of 2,900 U/ml and a sensitivity, a specificity and an accuracy of 68, 62 and 66%, respectively. Moreover, amylase with a cutoff of 6,800 U/l (sensitivity 66%, specificity 81% and accuracy 69%), CA72-4 with a cutoff of 7 U/ml (sensitivity 80%, specificity 61% and accuracy 72%), CA125 with a cutoff of 9 U/ml (sensitivity 83%, specificity 37% and accuracy 60%) and CA15-3 with a cutoff of 57 U/ml (sensitivity 19%, specificity 94% and accuracy 57%) have been defined. The cyst fluid amylase concentration has not been shown to distinguish MCNs from IPMNs. Cyst fluid cytokines and prostaglandins function as markers of inflammation, and pancreatitis can be a symptom of patients with IPMNs. Cytotoxic T cells and a decrease in CD8+ cells are characteristic of IPMNs. The methylation of the suppressor of cytokine signaling-1 (SOCS-1) is associated with 22% of PDACs and 6% of IPMNs. Prostaglandin E2 has to be validated as a reliable marker [19]. Interleukin 1β is differently expressed in high- and low-risk IPMNs, and in PDACs, there is a difference in glycan levels, which can be detected through serum analysis [10]. The interleukin 1β expression, with a cutoff of 1.26 pg/ml, a sensitivity of 54.4–93.9% and a specificity of 76.2–99.9%, shows differences in high- and low-risk cysts [20]. Interleukin 5 and 8 expression is also higher in high-grade dysplasia and invasive carcinoma [19]. MUC5AC is specific to mucinous cysts, with a sensitivity of 78% and a specificity of 80%. Combined with CA19-9 levels, a differentiation from serous cysts is certain with a sensitivity of 87% and a specificity of 86%. Endorepellin also helps to distinguish between high- and low-risk IPMNs, while plectin 1 is a potent marker for the identification of malignancy in mucinous cysts. The diagnosis of pancreatic cystic neoplasms can only be verified in 68% of preoperatively diagnosed patients [10]. In many cases, an association with inherited syndromes is possible, for example Peutz-Jeghers syndrome, familial pancreatic carcinomas and familial adenomatous polyposis [7, 3]. It is vital to mention that the major part of all diagnosed IPMNs are discovered incidentally in the course of an examination of the patient due to different reasons. The diagnostic techniques which are applied most often and are helpful for diagnosis involve ultrasonography, computed tomography, magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography (EUS) [3, 9]. Shi and Hruban [9] as well as Matthaei et al. [10] reviewed EUS fine-needle aspiration and cyst fluid analysis as possible techniques for diagnosis with quite good biomarkers. 18F-fluorodeoxyglucose positron emission tomography can also be useful. In clinical routine, MRI and MRCP are the primary diagnostic options [3]. In contrast to PanINs, IPMNs can be detected by imaging techniques because of their bigger size (>1 cm) [21]. The greater difficulty in diagnosing PanINs by imaging compared to IPMNs makes PanINs more dangerous because a late diagnosis increases the risk of an association with malignancy. The diagnostic identification of IPMNs is difficult because 9% of serous cystadenoma and 18% of MCNs communicate with the main pancreatic duct; therefore, imaging alone is not enough to identify the type of abnormality. In this case, the analysis of cyst fluid can be helpful [4].

Patients can greatly benefit from a diagnosis of IPMN at an early stage because precursor lesions can be treated quite well without the risk of an association with pancreatic cancer [21]. IPMNs grow slowly but can become invasive and produce metastases. The 5-year survival rate of IPMNs amounts to 50–80%. Surgical resection of noninvasive IPMNs increases survival rates to 90–100%. The surgical resection of IPMNs associated with invasive carcinoma results in a 5-year survival rate of 31–60% [4].

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Prognosis

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Eur Surg Res 2015;55:352–363 DOI: 10.1159/000441492

© 2015 S. Karger AG, Basel www.karger.com/esr

Benzel and Fendrich: Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Classification and Subtypes

Branch Duct IPMNs BD IPMNs (around 40% of all IPMNs) are cystic tumors within the side branches of the main pancreatic duct (

Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are noninvasive neoplasms which occur in the main pancreatic duct or its major branch...
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