Current understanding of precursors to pancreatic cancer

Precursors to pancreatic cancer have been investigated for a century. Previous studies have revealed three distinct precursors,i.e. mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), and pancreatic intraepithelial neoplasia (PanIN), harboring identical or similar genetic alterations as does invasive pancreatic carcinoma. The current understanding of precursors to pancreatic cancer can be illustrated by progressive pathways from noninvasive MCN, IPMN, and PanIN toward invasive carcinoma. MCNs consist of ovarian‐type stroma and epithelial lining with varying grades of atypia, and are occasionally associated with invasive adenocarcinoma. The epithelium of noninvasive IPMNs shows a variety of different directions of differentiation, including gastric, intestinal, pancreatobiliary (PB), and oncocytic types. IPMNs can also harbor varying grades of architectural and cytologic atypia. IPMNs confined to branch ducts are mostly the gastric type, and IPMNs involving the main ducts are often intestinal type, while PB and oncocytic types are rare. Small (<1 cm) IPMNs of the gastric type are not always morphologically distinguishable from low‐grade PanINs. Mucin expression profiles suggest intestinal‐type IPMNs progress to mucinous noncystic (colloid) carcinoma, while PB‐type IPMNs progress toward ductal adenocarcinoma. It is a well‐described paradigm that PanIN lesions progress toward ductal adenocarcinoma through step‐wise genetic alterations. The activation of Hedgehog and Notch signaling pathways in PanIN lesions as well as in pancreatic adenocarcinoma suggest that developmental pathways may be disregulated during carcinogenesis of the pancreas. Further study is needed to elucidate the pathways from precursors toward invasive carcinoma of the pancreas.     

Precancerous lesions of the pancreas

Pancreatic cancer has a very poor prognosis, with a five year survival of only 5%. New studies have shown that it takes over 11 years for cells to develop invasive capability. This provides an opportunity to intervene if precursor lesions can be detected. This paper reviews the molecular, pathological, clinical findings and management of pancreatic intraepithelial neoplasia (PanIN), intraductal pancreatic mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), three precursor lesions which can give rise to invasive carcinoma of the pancreas.     

Precursor lesions of pancreatic cancer: molecular pathology and clinical implications.

BACKGROUND: Pancreatic cancer is a lethal disease, with near uniform 5-year mortality rates. The key to improving survival of pancreatic cancer rests upon early detection of this neoplasm at a resectable, and hence potentially curable, stage. METHODS: We review the current state of the literature vis-à-vis the three common precursor lesions of pancreatic adenocarcinoma: pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. We also discuss two clinical scenarios of emerging importance, namely asymptomatic pancreatic cysts ('pancreatic incidentalomas') and the significance of precursor lesions in familial pancreatic cancer kindreds. RESULTS: Pancreatic intraepithelial neoplasias are the microscopic precursor lesions of pancreatic adenocarcinomas, while intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are macroscopic, cystic precursor lesions. All three noninvasive entities demonstrate a multistep morphologic and genetic progression that culminates in frank invasive adenocarcinoma. Despite these commonalities, each precursor lesion harbors a unique repertoire of clinicopathologic and genetic characteristics that has an impact on natural history and prognosis of these lesions. Due to improvements in radiological techniques, asymptomatic pancreatic cysts are being increasingly discovered in the general population; intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are the most common underlying histology in resected incidentalomas of the pancreas. Pancreatic asymptomatic cysts present an enormous challenge in terms of accurate diagnosis and management stratification. Incorporating molecular signatures of cystic precursor lesions into the diagnostic algorithm will likely become a standard of care for asymptomatic pancreatic cysts. High-risk individuals from familial pancreatic cancer kindreds are another group of individuals where knowledge of precursor lesions has had a therapeutic impact; sensitive imaging technologies have enabled the identification and subsequent resection of pancreatic cancer precursors in these high-risk individuals, preventing the progression to invasive cancer. CONCLUSIONS: Precursor lesions of pancreatic adenocarcinomas represent a unique opportunity for diagnosis and intervention for a malignancy with near uniform lethality. Further studies on these precursors will enable the development of rational early detection and therapeutic strategies in order to ameliorate pancreatic cancer survival.     

Management of intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a distinct entity characterized by papillary proliferations of mucin-producing epithelial cells with excessive mucus production and cystic dilatation of the pancreatic ducts. IPMNs have malignant potential and exhibit a broad histologic spectrum, ranging from adenoma to invasive carcinoma. IPMNs are classified into main duct and branch duct types, based on the site of tumor involvement. IPMN patients have a favorable prognosis if appropriately treated. The postoperative 5-year survival rate is nearly 100% for benign tumors and noninvasive carcinoma, and approximately 60% for invasive carcinoma. A main duct type IPMN should be resected. Surgical treatment is indicated for a branch duct IPMN with suspected malignancy (tumor diameter ≥ 30 mm, mural nodules, dilated main pancreatic duct, or positive cytology) or positive symptoms. Malignant IPMNs necessitate lymph node dissection (D1). IPMNs are associated with a high incidence of extrapancreatic malignancies and pancreatic ductal carcinoma.     

Helicobacter pylori is undetectable in intraductal papillary mucinous neoplasm

BackgroundAbout half of the world population is infected with Helicobacter pylori (H. pylori), a bacterium associated with gastric cancer and considered to be a risk factor for pancreatic ductal adenocarcinoma. Whether the bacterium is associated with intraductal papillary mucinous neoplasm, believed to be a precursor of pancreatic ductal adenocarcinoma, is unknown. The aim of this study was to investigate the presence of H. pylori DNA in tissue sections of intraductal papillary mucinous neoplasm.MethodsThe presence of H. pylori DNA was tested in a retrospective controlled study of formalin-fixed, paraffin-embedded pancreatic tissues from 24 patients who underwent surgery for intraductal papillary mucinous neoplasm. Histologically normal tissues surrounding neoplasms were used as control. H. pylori DNA was evaluated after deparaffinization, DNA extraction, and purification, and results were evaluated statistically.ResultsSamples were collected from 13 males and 11 females with mean age 59 years (range 44–77), and consisted of 19 cases of main-duct and three cases of branched-duct intraductal papillary mucinous neoplasm. Two patients were diagnosed with pancreatic cancer and main-duct intraductal papillary mucinous neoplasm. H. pylori DNA was not detected either in intraductal papillary mucinous neoplasm tissue, or in surrounding normal tissue.ConclusionsAlthough H. pylori has been implicated in pancreatic ductal adenocarcinoma, it may not play a key role in the development of intraductal papillary mucinous neoplasm.     

Precursors to pancreatic cancer

Infiltrating ductal adenocarcinoma of the pancreas is believed to arise from morphologically distinct noninvasive precursor lesions. These precursors include the intraductal papillary mucinous neoplasm, the mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia. Intraductal papillary mucinous neoplasms are grossly visible mucin-producing epithelial neoplasms that arise in the main pancreatic duct or one of its branches. The cysts of mucinous cystic neoplasms do not communicate with the major pancreatic ducts, and these neoplasms are characterized by a distinct ovarian-type stroma. Pancreatic intraepithelial neoplasia is a microscopic lesion. This article focuses on the clinical significance of these three important precursor lesions, with emphasis on their clinical manifestations, detection, and treatment.     

Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics

Mucinous cystic neoplasm (MCN) of the pancreas is a distinct clinicopathological entity characterized by mucin-producing epithelial and cyst-forming neoplasm with “ovarian-type” stroma beneath the epithelial component. It is clearly distinguished from ductal adenocarcinoma and intraductal papillary mucinous neoplasm (IPMN). However, MCN can progress to infiltrating carcinoma, and frequently shows a similar histological pattern to ductal adenocarcinoma. Several genetic alterations such as K-ras oncogene mutation, and epigenetic alterations such as hypermethylation of p16 in the invasive component of MCN are also common with ductal adenocarcinoma. Furthermore, recent technologies, including a laser-assisted microdissection system for histological slides and global gene expression profilings using DNA microarrays, made possible to identify more information about molecular abnormalities of MCNs. It is important to diagnose the lesions before they progress to an invasive carcinoma. MCN is one of the precursors of invasive pancreatic carcinoma.     

Multicentric pancreatic intraepithelial neoplasias (PanINs) presenting with the clinical features of chronic pancreatitis

A 46-year-old woman was readmitted to our hospital in August 2005 because of severe abdominal pain and nausea. Computed tomography demonstrated a huge cystic lesion in the retroperitoneal space behind the hepatoduodenal ligament and lesser peritoneal cavity. Endoscopic retrograde pancreatography revealed communication between the dilated main pancreatic duct and a pseudocyst. The condition was preoperatively diagnosed as chronic pancreatitis associated with a pseudocyst or an intraductal papillary mucinous neoplasm without mucin hypersecretion. The patient underwent a distal pancreatectomy with splenectomy. The pathologic diagnosis was multicentric pancreatic intraepithelial neoplasia (PanIN), and histological examination revealed a positive surgical margin around the remnant pancreas. Four months after the surgery, the patient underwent a total pancreatectomy. Macroscopic observation revealed diffuse fibrosis of the pancreatic parenchyma compatible with chronic pancreatitis. Histological examination revealed a constellation of noninvasive intraductal neoplasias with high-grade atypia, diffusely distributed in the small pancreatic ducts of the resected pancreas. Localized fibrosis and cystic dilation of the small ducts were detected in a lobule of exocrine glands draining into a ductule involved by PanIN lesions in the head of the pancreas. In summary, multicentric PanIN lesions are associated with lobular atrophy of the pancreatic parenchyma and chronic pancreatitis-like changes that follow. Total pancreatectomy may be recommended for patients with multicentric precursor lesions throughout the entire pancreas.     

Management of mucinous cystic neoplasms of the pancreas

The purpose of this study was to investigate the actual management of mucinous cystic neoplasm (MCN) of the pancreas. A systematic review was performed in December 2009 by consulting PubMed MEDLINE for publications and matching the "pancreatic mucinous cystic neoplasm", "pancreatic mucinous cystic tumour", "pancreatic mucinous cystic mass", "pancreatic cyst", and "pancreatic cystic neoplasm" to identify English language articles describing the diagnosis and treatment of the mucinous cystic neoplasm of the pancreas. In total, 16 322 references ranging from January 1969 to December 2009 were analysed and 77 articles were identified. No articles published before 1996 were selected because MCNs were not previously considered to be a completely autonomous disease. Definition, epidemiology, anatomopathological findings, clinical presentation, preoperative evaluation, treatment and prognosis were reviewed. MCNs are pancreatic mucinproducing cysts with a distinctive ovarian-type stroma localized in the body-tail of the gland and occurring in middle-aged females. The majority of MCNs are slow growing and asymptomatic. The prevalence of invasive carcinoma varies between 6% and 55%. Preoperative diagnosis depends on a combination of clinical features, tumor markers, computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound with cyst fluid analysis, and positron emission tomography-CT. Surgery is indicated for all MCNs.     

Intraductal papillary mucinous neoplasm of the biliary tract with cardiac metastasis: A case report

Introduction:Intraductal papillary mucinous neoplasm of the biliary tract (IPNB) is a rare, low-grade neoplasm limited to the bile duct mucosa. The malignant transformation rate is low, and there have been limited reports of metastasis to other organs. Herein, we presented a rare case of a patient who was diagnosed with IPNB concurrent with invasive adenocarcinoma after surgery and was diagnosed with cardiac metastasis 6 months later.Patient concerns:A 61-year-old male patient presented with abdominal pain to a local clinic. He was diagnosed with intrahepatic cholangiocarcinoma with pancreatitis and transferred to our hospital.Diagnosis:Diagnostic testing (magnetic resonance imaging, endoscopic retrograde cholangiopancreatography, positron emission tomography-computed tomography) revealed a papillary neoplasm and invasive adenocarcinoma with papillary neoplasm in the periampullary lesion.Interventions:Pancreaticoduodenectomy, right hemihepatectomy, and left lateral sectionectomy of the liver were performed. After surgery, we planned gemcitabine-based adjuvant chemotherapy.Outcomes:Upon completion of the sixth gemcitabine chemotherapy cycle, a hyperechoic, oval-shaped mass (1.3 × 2.6 cm) was found on the outer wall of the right atrium. Resection of a cardiac tumor in the right atrium and patch repair were performed.Conclusion:To our knowledge, no other case of cardiac metastasis found during observation after surgery for an IPNB has been described. IPNBs are known to be less aggressive and to have a lower metastasis rate than intraductal papillary mucinous neoplasms; therefore, the number of case reports describing metastasis after surgery is relatively low. Our case suggests that close observation is necessary in patients diagnosed with an IPNB.     

胰腺癌前病变诊断和治疗

目的 通过对7例胰腺癌前病变患者的临床诊断和治疗分析,探讨此类疾病诊断方法的应用及治疗策略.方法 收集2006年1月-2007年12月92例手术治疗胰腺肿瘤中有癌前病变的7例患者,其中黏液囊腺瘤(MCN)1例、导管内乳头状黏液瘤(IPMN)2例、胰腺内分泌肿瘤1例、胰腺上皮内瘤变(PanIN)Ⅰ级、Ⅱ级及Ⅲ级各1例.采用免疫荧光分析法测定患者血清CA19-9.7例上腹部均行超声和螺旋CT检查;1例行超声内镜检查及穿刺;2例行逆行胰胆管造影检查.结果 胰腺癌前病变临床表现不典型,影像学检查常无实质性肿块,但PanIN可伴有胰管扩张、狭窄;IPMN在胰头处可表现为囊性扩张的胰管;囊腺瘤等在胰体尾处可表现为单个孤立的囊肿.肿瘤指标CA19-9在此类疾病中可轻度增高.但对诊断作用有限.手术切除可治愈,并可防止肿瘤的进一步癌变.结论 对疑为胰腺癌前病变患者需积极选用多种影像学方法进行诊断,并予以积极的手术探查及切除.     

Study of recurrence after surgical resection of intraductal papillary mucinous neoplasm of the pancreas

BACKGROUND & AIMS: The aim of this study was to determine recurrence and long-term survival after resection of pancreatic intraductal papillary mucinous neoplasm and to correlate recurrence and survival with histology, extent of resection, and duration of follow-up. METHODS: A single pathologist, without knowledge of previous interpretations of histology or clinical data, retrospectively reviewed and classified 113 resected intraductal papillary mucinous neoplasms as invasive carcinoma (n = 40) or as noninvasive neoplasms (adenoma, borderline, or carcinoma in situ; n = 73). Data on recurrence (locoregional or metastatic), follow-up, and cause of death were obtained from patient records and/or by contacting patients and their physicians. RESULTS: In invasive intraductal papillary mucinous neoplasm, recurrence was similar after partial pancreatectomy (18/27; 67%) and total pancreatectomy (8/13; 62%) and occurred within 3 years of resection in 91%. Among noninvasive neoplasms, 5 of 60 (8%) recurred after partial pancreatectomy (median follow-up, 37 months); none recurred after total pancreatectomy (n = 13; median follow-up, 32 months). Recurrence after resection in noninvasive neoplasms was diagnosed after a median of 40 months (range, 23-75 months); recurrence was noninvasive in 3 and invasive cancer in 2. Five-year survival was better for noninvasive compared with invasive intraductal papillary mucinous neoplasm (84.5% vs. 36%; P < 0.001). CONCLUSIONS: Invasive intraductal papillary mucinous neoplasm recurs frequently even after a complete "curative" resection and portends poor survival. In contrast, noninvasive intraductal papillary mucinous neoplasm recurs infrequently after resection, and survival is excellent regardless of the degree of epithelial dysplasia in the tumor.     

Intraductal papillary mucinous neoplasm of the biliary tract: a real disease?

Background:

Despite increasing numbers of reports, biliary tract intraductal papillary mucinous neoplasm (BT-IPMN) is not yet recognized as a unique neoplasm. The aim of the present study was to define the presence of BT-IPMN in a large series of resected biliary neoplasms.

Methods:

From May 1994 to December 2006, BT-IPMN cases were identified by reviewing pathology specimens of all resected cholangiocarcinomas and other biliary neoplasms when cystic, papillary or mucinous features were cited in pathology reports.

Results:

BT-IPMN was identified in 23 out of 253 (9%) specimens using the strict histopathological criteria of IPMN. The most common presenting symptom was abdominal discomfort which was present in 15 patients (65%). Only one of the original operative pathology reports used the term IPMN; 16 (70%) used the terms cystic, mucinous and/or papillary. BT-IPMN was isolated to non-hilar extra-hepatic ducts in 12 (52%), intra-hepatic ducts in 6 (26%) and hilar extra-hepatic ducts in 5 patients (22%). Carcinoma was found in association with BT-IPMN in 19 patients (83%); 5-year survival was 38% after resection.

Conclusion:

BT-IPMN occurs throughout the intra- and extra-hepatic biliary system and can be identified readily as a unique neoplasm. Broader acceptance of BT-IPMN as a unique neoplasm may lead to a better understanding of the pathogenesis of biliary malignancies.     

CLINICAL SIGNIFICANCE OF INTRADUCTAL ULTRASONOGRAPHY FOR DIAGNOSIS OF INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM OF THE PANCREAS

Intraductal ultrasonography (IDUS) is useful for evaluating the horizontal spread along the main pancreatic duct in cases of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, thus providing valuable information for the determination of the resection line at surgery. Differentiation between benign and malignant IPMN is also indispensable for management decisions. Measurement of the height of mural nodules by IDUS is expected to be useful for differential diagnosis of IPMN. Because IDUS cannot always demonstrate whole lesions, especially in branch duct IPMN, endoscopic ultrasonography plays a complementary role in such cases.     

Intraductal Papillary Mucinous Neoplasm with Pancreatogastric Fistula

We herein report a rare case of intraductal papillary mucinous neoplasm with a pancreatogastric fistula in an elderly Japanese man admitted to our hospital. The pancreatogastric fistula was confirmed using endoscopic retrograde pancreatography via a cannulated guidewire placed in the stomach. Six months after admission, the patient was diagnosed with intraductal papillary mucinous carcinoma. A pancreatogastric fistula is generally a rare complication of intraductal papillary mucinous neoplasm. It was caused by mechanical penetration in this case. Interestingly, we also observed endoscopic and histochemical mucosal changes in the fistula.     

Intraductal papillary mucinous tumors and mucinous cystic tumors of the pancreas: imaging

Most cystic lesions of the pancreas are nonneoplastic and inflammatory in nature. However, approximately 5%–15% of cystic pancreatic masses may be neoplastic. Among the cystic neoplasms are the mucin-producing tumors, both the intraductal papillary mucinous neoplasms and the mucinous cystic neoplasms. Their imaging features on contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) can assist in the differentiation of these lesions. The imaging findings of both intraductal papillary mucinous neoplasm and mucinous cystic neoplasm are reviewed with attention to CT and MRI.     

Inferior head resection of the pancreas for intraductal papillary mucinous neoplasms

Background

Previous reports have suggested that patients with intraductal papillary mucinous neoplasm (IPMN) have a favorable prognosis after surgical resection. Thus, a variety of types of partial pancreatic resections have been advocated for treating these low-grade malignant tumors. However, the surgical outcome of IPMN after such limited pancreatectomy has not been fully clarified.

Methods

We performed a retrospective review of the clinicopathologic features and surgical outcome in 15 patients who underwent inferior head resection for IPMN at the Chiba University Hospital and National Cancer Center Hospital East between July 1994 and January 2007.

Results

There were 13 patients with noninvasive IPMNs (10 adenomas and 3 noninvasive carcinomas) and 2 patients with minimally invasive intraductal papillary mucinous carcinoma (minimally invasive IPMN). Complete tumor removal (R0 resection) was performed in four patients (80%) with intraductal papillary mucinous carcinoma. Subsequent pancreatoduodenectomy was performed in one patient because of noninvasive carcinoma with multiple mucous lakes in the pancreatic parenchyma. Values for N-benzoyl-l-tyrosyl-p-aminobenzoic acid excretion test results before (n?=?13) and after (n?=?13) the operation were 70.7 and 66.1, showing no significant difference. The 2-h glucose levels in the 75?g oral glucose tolerance test before (n?=?13) and after (n?=?13) the operation were 133 and 146?mg/dl, respectively, showing no significant difference. Pancreatic fistula occurred in 7 (47%) patients. Overall morbidity and mortality rates were 67 and 0%, respectively. The overall 1-, 3-, 5-, and 10-year survival rates for the 15 patients were 100, 79, 79, and 71%, respectively. The 1-, 3-, 5-, and 10-year survival rates for patients with noninvasive IPMN (n?=?13) and those with minimally invasive IPMN (n?=?2) were 100, 92, 92, and 83%; and 100, 0, 0, and 0%, respectively. There was a significant difference in survival between patients with noninvasive IPMN and those with minimally invasive IPMN (p?=?0.0005). No patient with noninvasive IPMN developed recurrent disease. One patient with minimally invasive IPMN died of recurrent peritoneal dissemination 18?months after margin-positive R1 resection. Two patients died of pancreatic ductal adenocarcinoma, 30 and 78?months after inferior head resection.

Conclusions

Pancreatic endocrine and exocrine function was well preserved after inferior head resection. Pancreatic fistula occurred more frequently after inferior head resection than with conventional pancreatoduodenectomy. Patients with noninvasive IPMN had favorable survivals after this procedure. However, one patient with minimally invasive IPMN with margin-positive R1 resection died of recurrent disease. Thus, margin-negative R0 resection should be performed for IPMN.     

Cystic pancreatic lesions: Current evidence for diagnosis and treatment

Abstract

Pancreatic cystic neoplasms are detected at an increasing frequency due to an increased use and quality of abdominal imaging. There are well known differential diagnostic difficulties concerning these lesions. The aim is to review current literature on the diagnostic options and the following treatment for cystic lesions in the pancreas focusing on serous cystadenomas, primary mucinous neoplasm of the pancreas and mucinous cystadenocarcinomas, as well as intraductal papillary mucinous neoplasms, starting with excluding pseudocysts. A conservative approach is feasible in patients with a clinical presentation suggestive of an asymptomatic serous cystadenoma. Surgical management, as well as follow-up, is discussed for each of the types of neoplastic lesions, including an uncharacterized cyst, based on patient data, symptoms, serum analysis, cyst fluid analysis and morphological features. Aspects for future diagnostics and management of these neoplasia are commented upon.     

胰腺导管内乳头状黏液瘤

胰腺导管内乳头状黏液瘤（IPMN）是由胰腺导管内产生黏液的上皮细胞呈乳头状增殖形成的肿瘤。与经典的胰腺癌相比,IPMN具有低度恶性、生长缓慢、少有侵犯周围组织、淋巴结转移率和再发率低的特点。IPMN根据肿瘤累及的部位可分为主胰管型、分支胰管型和混合型,病理组织特征涵盖从单纯腺瘤到浸润癌等多个亚型,临床表现多样,多种影像学检查手段可显示弥漫性或节段性扩张的主胰管和囊状扩张的分支胰管,ERCP经扩大的乳头获取黏液和胰液,取胰腺导管内皮组织和壁结节供活检均有助于诊断。IPMN确诊后应积极手术,手术切除率高,术后5年生存率高于一般的胰腺癌。本文就其临床表现、分类、病理特征、影像学诊断和治疗等方面做一综述。     

Mucin expression profile in pancreatic cancer and the precursor lesions

In this review article, we demonstrate the mucin expression profile in normal tissue, invasive ductal carcinoma (IDC), two subtypes of intraductal papillary–mucinous neoplasm (IPMN dark cell type and IPMN clear cell type), pancreatic intraepithelial neoplasia (PanIN), and mucinous cystic neoplasm (MCN) of the pancreas. In MUC1, there are various glycoforms, such as poorly glycosylated MUC1, sialylated MUC1, and fully glycosylated MUC1. IDCs showed high expression of all the glycoforms of MUC1. IPMNs dark cell type showed no expression or low expression of all the glycoforms of MUC1. IPMNs clear cell type showed low expression of poorly glycosylated MUC1, but expression of sialylated MUC1 and fully glycosylated MUC1. Expression of MUC2 was negative in IDCs, high in IPMNs dark cell type and low in IPMNs clear cell type. MUC5AC was highly expressed in IDCs, IPMNs dark cell type, and IPMNs clear cell type. MUC6 expression was higher in IPMNs clear cell type than in IDCs and IPMNs dark cell type. Our recent study demonstrated that high expression of MUC4 in IDCs is correlated with a poor outcome for patients. In PanINs, expression of both MUC5AC and MUC6 are an early event, whereas up-regulation of MUC1 is a late event. MCNs do not look as if they will show a specific mucin expression profile according to the literature review.