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Manne A, Yu L, Hart PA, Tsung A, Esnakula A. Differential Expression and Diagnostic Value of MUC5AC Glycoforms in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:4832. [PMID: 37835525 PMCID: PMC10571547 DOI: 10.3390/cancers15194832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 09/22/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
We explored the differential expression and diagnostic value of two significant Mucin 5AC (MUC5AC) glycoforms, less-glycosylated immature (IM) and heavily-glycosylated mature (MM), in neoplastic diseases (NpD), including pancreatic ductal adenocarcinoma (PDA) and neuroendocrine tumors (NET), and non-neoplastic (non-NpD) diseases. Commercially available tissue microarray (TMA) was constructed from 96 patients, including 38 primary PDA (PT), 5 metastatic lesions (ML), 11 NET, and the rest being non-NpD tissues. Immunohistochemistry for MUC5AC was performed using CHL2 and 45M1 clones for IM and MM isoforms, respectively. MUC5AC (both glycoforms) are not detected in non-NpD. In MUC5AC-positive neoplastic tissues, IM was localized to the cytoplasm (Cy) while MM was identified in apical (Ap) and extracellular (Ec) regions too. One ML positive (omentum) in the TMA expressed both. For PDA vs. non-PDA, the sensitivity (SN) was higher with MM ± IM (71%) than MM (47%) or IM (65%)-alone. The specificity (SP) was 100% with MM-alone, which dropped with the addition of IM (96%) or IM-alone (93%). For NpD vs. non-NpD, the SN (MM + IM-59%, IM-55%, MM-37%) was inferior, and SP was 100% for both glycoforms (MM ± IM). The combination of MUC5AC glycoforms has high SP and reasonable SN to diagnose PDA. They have the potential to be a reliable diagnostic marker and should be investigated further in more extensive studies.
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Affiliation(s)
- Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Lianbo Yu
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Allan Tsung
- Department of Surgery, University of Virginia Health, Charlottesville, VA 22908, USA
| | - Ashwini Esnakula
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Kubo N, Yazawa S, Yokobori T, Sano R, Eguchi H, Kobayashi S, Akita H, Mitsufuji S, Yamashita YI, Nakao Y, Fujii T, Okumura T, Shibuya K, Hoshino Y, Yamada S, Hayashi M, Shimokawa M, Shirabe K. The malignant potential of pancreatic intraductal papillary mucinous neoplasm is reflected in expression levels of fucosylated glycans in α 1 -acid glycoprotein. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 30:503-513. [PMID: 35776060 DOI: 10.1002/jhbp.1208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/07/2022] [Accepted: 06/03/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND Pancreatic intraductal papillary mucinous neoplasm (IPMN) involves multiple histopathological stages from benign to malignant lesions. Further, a biomarker to diagnose the malignant IPMN (IPMC) is clinically relevant. Recently, we found that serum fucosylated α1 -acid glycoprotein (fAGP) level markedly elevated along with disease progression in large cohorts of patients with various cancers. METHODS The fAGP level was retrospectively analyzed in preoperative sera from 109 patients with IPMN, and the clinical relevance of fAGP was compared with currently available predictors as standard. RESULTS The fAGP level in IPMC was found to be significantly higher than in benign IPMN (P=0.0012). At a cutoff value of 27.04 U/μg, its sensitivity, specificity, and accuracy for IPMC were determined to be 83.61, 65.96 and 75.93%, respectively. Multivariate analyses revealed that the fAGP level was the only independent risk factor for predicting IPMC. Additionally, a combination of the fAGP level and 18 F-fluorodeoxyglucose uptake on the PET/CT imaging in the lesions seemed to offer the best diagnosis of IPMN. Accordingly, 27 of the 28 patients who were positive in both tests had IPMC, while patients who are negative had benign IPMN. CONCLUSIONS The fAGP level appeared to be a relevant biomarker for malignant potential of IPMN.
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Affiliation(s)
- Norio Kubo
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Shin Yazawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Takehiko Yokobori
- Department of Innovative Cancer Immunotherapy, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Rie Sano
- Department of Legal Medicine, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Suguru Mitsufuji
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yosuke Nakao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Tsutomu Fujii
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Tomoyuki Okumura
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Kazuto Shibuya
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Yui Hoshino
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mototsugu Shimokawa
- Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
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Syrkina MS, Rubtsov MA. MUC1 in Cancer Immunotherapy - New Hope or Phantom Menace? BIOCHEMISTRY (MOSCOW) 2019; 84:773-781. [PMID: 31509728 DOI: 10.1134/s0006297919070083] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Understanding of the functioning of MUC1 (human mucin) has advanced significantly over 40 years of its investigation. The anti-adhesive properties of the extracellular domain, which were the main focus of early studies initially explaining overexpression of MUC1 in progressing oncological diseases, were gradually put on the back burner. Researchers became more interested in its regulatory and signaling functions in cells rather in its anti-adhesive properties. The found the ability of MUC1 for signal transduction, and its ability to participate in cell metabolism opened new possibilities for improved control over cancer cells in addition to just attracting antigens of the immune system to a target. Nevertheless, there are issues in the functioning of MUC1 that raise doubts about its effectiveness in cancer immunotherapy.
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Affiliation(s)
- M S Syrkina
- Lomonosov Moscow State University, Department of Biology, Moscow, 119234, Russia. .,Lomonosov Moscow State University, Laboratoire Franco-Russe de Recherches en Oncologie, Moscow, 119234, Russia
| | - M A Rubtsov
- Lomonosov Moscow State University, Department of Biology, Moscow, 119234, Russia. .,Lomonosov Moscow State University, Laboratoire Franco-Russe de Recherches en Oncologie, Moscow, 119234, Russia.,Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia
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Yamashita H, Kurita A, Azuma S, Kudo Y, Matsuzaki N, Yazumi S. Usefulness of immunohistochemical staining for MUC5AC in differentiating primary pancreatic cancer from pancreatic metastasis of breast cancer. Diagn Cytopathol 2019; 47:1037-1041. [PMID: 31169985 DOI: 10.1002/dc.24249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 12/27/2018] [Accepted: 05/23/2019] [Indexed: 11/09/2022]
Abstract
Diagnosis of pancreatic ductal adenocarcinoma (PDAC) and its differentiation from metastases to the pancreas from other organs remains challenging. We report a case in which immunohistochemical staining for MUC5AC was useful in distinguishing primary pancreatic cancer from breast cancer metastasis. A 51-year-old Japanese woman who underwent curative resection of her breast cancer was referred to our hospital with a pancreatic head tumor. Although we surmised her pancreatic tumor to be metastatic breast cancer based on her past history and imaging studies, she was subsequently diagnosed with PDAC on the basis of immunohistochemical staining for MUC5AC using specimens obtained by endoscopic ultrasound-fine-needle aspiration. Thus, MUC5AC may be a useful diagnostic marker for discriminating PDAC from a secondary malignancy.
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Affiliation(s)
- Hiroki Yamashita
- Department of Gastroenterology and Hepatology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Akira Kurita
- Department of Gastroenterology and Hepatology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Shunjiro Azuma
- Department of Gastroenterology and Hepatology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Yasushi Kudo
- Department of Gastroenterology and Hepatology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | | | - Shujiro Yazumi
- Department of Gastroenterology and Hepatology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
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Klausen P, Kovacevic B, Toxvaerd A, Kalaitzakis E, Karstensen JG, Rift CV, Hansen CP, Storkholm J, Vilmann P, Hasselby JP. Subtyping of intraductal papillary mucinous neoplasms - pitfalls of MUC1 immunohistochemistry. APMIS 2018; 127:27-32. [PMID: 30549137 DOI: 10.1111/apm.12900] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 09/08/2018] [Indexed: 12/18/2022]
Abstract
Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic ductal adenocarcinoma (PDAC). Current edition of WHO Classification of Tumors of the Digestive System recognizes four different subtypes (gastric, intestinal, pancreatobiliary, and oncocytic) and recommends analysis of mucin expression (MUC1, MUC2, MUC5AC, MUC6) as well as evaluation of architectural and cell differentiation patterns for correct classification. However, there is no consensus on MUC1 expression of IPMN-lesions in the literature. Current recommendations are based on studies where antibodies against the core MUC1 protein or sialylated MUC1 (tumor associated MUC1), not the fully glycosylated MUC1 were used. We have recently reported that MUC1 is strongly expressed in both gastric and intestinal types IPMN specimens from the cystic wall, obtained by endoscopic ultrasound guided microbiopsy procedure. We have used a commercial MUC1 antibody, validated and recommended for diagnostic use, which recognizes fully glycosylated MUC1. Based on the above, we propose a revision of the WHO Classification, specifying that antibodies against tumor associated MUC1 should be used for IPMN subtyping.
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Affiliation(s)
- Pia Klausen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Bojan Kovacevic
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Anders Toxvaerd
- Department of Pathology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Evangelos Kalaitzakis
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - John Gásdal Karstensen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark.,Gastro Unit, Division of Surgery, Copenhagen University Hospital Hvidovre, Herlev, Denmark
| | - Charlotte Vestrup Rift
- Department of Pathology, Copenhagen University Hospital Rigshospitalet, København, Denmark
| | - Carsten Palnaes Hansen
- Department of Gastrointestinal Surgery, Copenhagen University Hospital Rigshospitalet, København, Denmark
| | - Jan Storkholm
- Department of Gastrointestinal Surgery, Copenhagen University Hospital Rigshospitalet, København, Denmark
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Jane Preuss Hasselby
- Department of Pathology, Copenhagen University Hospital Rigshospitalet, København, Denmark
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Quantitative proteomic analysis of pancreatic cyst fluid proteins associated with malignancy in intraductal papillary mucinous neoplasms. Clin Proteomics 2018; 15:17. [PMID: 29713252 PMCID: PMC5907296 DOI: 10.1186/s12014-018-9193-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 04/04/2018] [Indexed: 12/13/2022] Open
Abstract
Background
The application of advanced imaging technologies for identifying pancreatic cysts has become widespread. However, accurately differentiating between low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive intraductal papillary mucinous neoplasms (IPMNs) remains a diagnostic challenge with current biomarkers, necessitating the development of novel biomarkers that can distinguish IPMN malignancy.
Methods Cyst fluid samples were collected from nine IPMN patients (3 LGD, 3 HGD, and 3 invasive IPMN) during their pancreatectomies. An integrated proteomics approach that combines filter-aided sample preparation, stage tip-based high-pH fractionation, and high-resolution MS was applied to acquire in-depth proteomic data of pancreatic cyst fluid and discover marker candidates for IPMN malignancy. Biological processes of differentially expressed proteins that are related to pancreatic cysts and aggressive malignancy were analyzed using bioinformatics tools such as gene ontology analysis and Ingenuity pathway analysis. In order to confirm the validity of the marker candidates, 19 cyst fluid samples were analyzed by western blot.
Results A dataset of 2992 proteins was constructed from pancreatic cyst fluid samples. A subsequent analysis found 2963 identified proteins in individual samples, 2837 of which were quantifiable. Differentially expressed proteins between histological grades of IPMN were associated with pancreatic diseases and malignancy according to ingenuity pathway analysis. Eighteen biomarker candidates that were differentially expressed across IPMN histological grades were discovered—7 DEPs that were upregulated and 11 that were downregulated in more malignant grades. HOOK1 and PTPN6 were validated by western blot in an independent cohort, the results of which were consistent with our proteomic data. Conclusions This study demonstrates that novel biomarker candidates for IPMN malignancy can be discovered through proteomic analysis of pancreatic cyst fluid. Electronic supplementary material The online version of this article (10.1186/s12014-018-9193-1) contains supplementary material, which is available to authorized users.
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Abstract
OBJECTIVES Reprimo gene is a cytoplasmic protein belonging to a family of molecules controlled by p53 that inhibits cell cycle progression. Ectopic expression of Reprimo results in cell cycle arrest at the G2 phase. The aim of this study was to investigate the impact of Reprimo expression on tumorigenesis of intraductal papillary mucinous neoplasm (IPMN). METHODS Thirty-seven surgical cases of IPMN were collected retrospectively. Twenty-eight patients had benign IPMNs (low-grade dysplasia, n = 18; intermediate-grade dysplasia, n = 10), and the remaining 9 had malignant IPMNs (high-grade dysplasia, n = 4; invasive carcinoma, n = 5). DNA from tumor samples was extracted. DNA methylation patterns of Reprimo were determined by the methods of methylation-specific polymerase chain reaction and immunohistochemistry. The methylation status of Reprimo was compared between benign IPMNs and malignant IPMNs. RESULTS The incidence of aberrant DNA methylation of Reprimo was significantly higher in malignant IPMNs than in benign IPMNs (78% vs 32%, P = 0.016). Furthermore, the incidence of immunohistochemical Reprimo expression was significantly lower in malignant IPMNs than in benign IPMNs (22% vs 82%, P = 0.002). CONCLUSIONS Reprimo methylation was found more frequently in malignant IPMNs. Reprimo methylation is involved in malignant transformation of IPMNs.
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Moschovis D, Bamias G, Delladetsima I. Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol 2016; 8:725-734. [PMID: 27795812 PMCID: PMC5064050 DOI: 10.4251/wjgo.v8.i10.725] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/19/2016] [Accepted: 08/15/2016] [Indexed: 02/05/2023] Open
Abstract
Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.
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Sierzega M, Młynarski D, Tomaszewska R, Kulig J. Semiquantitative immunohistochemistry for mucin (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6) profiling of pancreatic ductal cell adenocarcinoma improves diagnostic and prognostic performance. Histopathology 2016; 69:582-91. [PMID: 27165582 DOI: 10.1111/his.12994] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 05/06/2016] [Indexed: 02/04/2023]
Abstract
AIMS Mucin (MUC) glycoproteins are involved in various steps of the carcinogenesis and progression of human malignancies. The aim of this study was to verify whether semiquantitative evaluation of MUC staining by immunohistochemistry may help to differentiate pancreatic ductal cell adenocarcinoma (PDAC) from chronic pancreatitis and normal pancreas. METHODS AND RESULTS Mucin expression was examined by immunohistochemistry in surgical specimens resected from 101 patients with PDAC and 33 with chronic pancreatitis, and in 40 normal pancreatic tissue specimens. A quickscore (QS, range 0-300) was calculated by multiplying staining intensity by the percentage of positive cells. A diagnostic model was developed for MUC QS (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6), based on a receiver operating characteristic (ROC) curve and logistic regression analysis. Median QS values for MUC1 and MUC5AC were significantly higher for PDAC, whereas patients with non-malignant tissues had higher values for MUC3 and MUC6. The area under the curve for the ROC curve derived from the diagnostic model including MUC3, MUC5AC and MUC6 was 0.96 [95% confidence interval (CI) 0.91-0.98], with 85% sensitivity and 94% specificity. Median QS values for MUC2 were significantly higher in patients with less advanced tumours, whereas venous invasion was associated with a lower QS for MUC6. Moreover, multivariate survival analysis revealed that low MUC6 expression was a negative prognostic factor, with a hazard ratio of 1.73 (95% CI 1.07-2.81). CONCLUSIONS The three-MUC diagnostic model (MUC3, MUC5AC, and MUC6) showed an excellent ability to discriminate pancreatic cancer from non-malignant tissues, and yielded information that may prove useful for the development of clinical applications.
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Affiliation(s)
- Marek Sierzega
- First Department of Surgery, Jagiellonian University Medical College, Krakow, Poland.
| | - Damian Młynarski
- Department of Pathology, Jagiellonian University Medical College, Krakow, Poland
| | - Romana Tomaszewska
- Department of Pathology, Jagiellonian University Medical College, Krakow, Poland
| | - Jan Kulig
- First Department of Surgery, Jagiellonian University Medical College, Krakow, Poland
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A case of MUC5AC-positive intraductal neoplasm of the pancreas classified as an intraductal tubulopapillary neoplasm? Pathol Res Pract 2015; 211:1034-9. [PMID: 26586167 DOI: 10.1016/j.prp.2015.10.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 10/04/2015] [Accepted: 10/25/2015] [Indexed: 01/04/2023]
Abstract
This report describes a unique case of intraductal tubulopapillary neoplasm (ITPN) of the pancreas in order to clarify its oncogenesis and more precisely classify pancreatic intraductal neoplasms. A 74-year-old man visited our institution for follow-up of acute pancreatitis. Imaging examinations revealed a hypovascular intraductal mass in the head of the pancreas with progressive dilation of the pancreatic duct, atrophy of the pancreatic parenchyma, and a non-mucinous appearance. A pancreatoduodenectomy was performed to identify this pancreatic intraductal neoplasm. Macroscopically, the tumor was a solid nodular mass with no visibly secreted mucin obstructing the dilated ducts. Histologically, it had a homogeneous appearance with nodules of back-to-back tubular glands and occasional papillary elements, and there were no apparent transitions to areas with less marked cytoarchitectural atypia. Although the intraductal neoplastic growth corresponded to an ITPN, immunohistochemical staining revealed partial positivity for MUC5AC, for which ITPNs are characteristically negative. Somatic mutations in KRAS, GNAS, BRAF, and PIK3CA were not detected. A loss of MUC5AC expression and mutations in KRAS and GNAS are key elements in the diagnosis of ITPN. Thus, it was difficult to distinguish the present case as a pancreatobiliary-type (PB-type) intraductal papillary mucinous neoplasm (IPMN) or a phenotypic variant of ITPN. As it is possible that some cases of PB-type IPMN and ITPN overlap, the precise classification of these rare lesions may require re-evaluation.
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Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma. Pancreas 2015; 44:728-34. [PMID: 25906442 PMCID: PMC4464972 DOI: 10.1097/mpa.0000000000000362] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). METHODS Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features. RESULTS The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002). CONCLUSIONS Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.
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12
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Inagaki Y, Seyama Y, Hasegawa K, Tang W, Kokudo N. Subcellular localization of KL-6 mucin in intraductal papillary mucinous neoplasm of the pancreas. Drug Discov Ther 2014; 8:173-7. [PMID: 25047009 DOI: 10.5582/ddt.2014.01027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
This study aimed to clarify the expression profile of KL-6 mucin in intraductal papillary mucinous neoplasm (IPMN) and its relation to tumor malignancy. Expression of KL-6 mucin in 38 IPMNs (intraductal papillary mucinous adenoma (IPMA), 24 cases; minimally invasive intraductal papillary mucinous carcinoma (MI-IPMC), 8 cases; invasive carcinoma originating from IPMC (IC-IPMC), 6 cases) and 66 pancreatic ductal adenocarcinomas (PDACs) was evaluated immunohistochemically. IC-IPMCs and MI-IPMCs had positive staining of KL-6 mucin whereas 58% of IPMAs tested negative. Subcellular localization of KL-6 mucin varied among IPMNs whereas all of the PDAC had positive expression in the circumferential membrane and cytoplasm of cancer cells. IC-IPMCs and MI-IPMCs had a higher frequency of circumferential membrane and cytoplasmic localization of KL-6 mucin than did IPMAs. These results suggest that localization of KL-6 mucin could be used to predict the malignancy of IPMN.
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Affiliation(s)
- Yoshinori Inagaki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo
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Yokoyama S, Kitamoto S, Higashi M, Goto Y, Hara T, Ikebe D, Yamaguchi T, Arisaka Y, Niihara T, Nishimata H, Tanaka S, Takaori K, Batra SK, Yonezawa S. Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice. PLoS One 2014; 9:e93760. [PMID: 24714692 PMCID: PMC3979708 DOI: 10.1371/journal.pone.0093760] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 03/06/2014] [Indexed: 12/19/2022] Open
Abstract
Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel 'methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.
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Affiliation(s)
- Seiya Yokoyama
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Sho Kitamoto
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Michiyo Higashi
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Yuko Goto
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Taro Hara
- Division of Endoscopy, Chiba Cancer Center, Chiba, Chiba, Japan
| | - Dai Ikebe
- Division of Surgical Pathology, Chiba Cancer Center, Chiba, Chiba, Japan
| | - Taketo Yamaguchi
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Chiba, Japan
| | - Yoshifumi Arisaka
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Toru Niihara
- Division of Gastroenterology, Nanpuh Hospital, Kagoshima, Kagoshima, Japan
| | - Hiroto Nishimata
- Division of Gastroenterology, Nanpuh Hospital, Kagoshima, Kagoshima, Japan
| | - Sadao Tanaka
- Division of Surgical Pathology, Nanpuh Hospital, Kagoshima, Kagoshima, Japan
| | - Kyoichi Takaori
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
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Expression of MUC4 mucin is observed mainly in the intestinal type of intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2013; 42:1120-8. [PMID: 23921963 PMCID: PMC3779537 DOI: 10.1097/mpa.0b013e3182965915] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES This study aimed to examine expression profile of MUC4 in intraductal papillary mucinous neoplasm of the pancreas (IPMN). METHODS We performed immunohistochemistry (IHC) of MUC4 in 142 IPMNs, with evaluation of the specificity of 2 anti-MUC4 monoclonal antibodies, 8G7 and 1G8, in cancer cell lines. RESULTS Monoclonal antibody 8G7 showed a clear immunoreactivity, whereas MAb 1G8 did not show any immunoreactivity, in the Western blotting and IHC for human pancreatic carcinoma cell lines expressing MUC4 messenger RNA. However, IHC signals detected by both monoclonal antibodies were observed in the tissue specimens. The expression rates of MUC4/8G7 detected by MAb 8G7 and MUC4/1G8 detected by MAb 1G8 in the intestinal-type IPMNs were significantly higher than those in the gastric-type IPMNs. In the intestinal-type IPMNs, MUC4/8G7 was expressed mainly in the cytoplasm of the neoplastic cells, whereas MUC4/1G8 was expressed mainly at the cell apexes. Even in the gastric-type IPMNs with rare MUC4 expression in the low-grade dysplasia, both MUC4 expression rates increased when dysplasia advanced. CONCLUSIONS A significantly higher expression of MUC4 in intestinal-type IPMNs than in gastric-type IPMNs will be one of the biomarkers to discriminate between the intestinal-type IPMNs with high malignancy potential from gastric-type IPMNs with low malignancy potential.
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Masuda A, Arisaka Y, Hara S, Matsumoto I, Takenaka M, Sakai A, Shiomi H, Matsuki N, Sugimoto M, Fujita T, Hayakumo T, Ku Y, Ogino S, Azuma T, Kutsumi H. MUC2 expression and prevalence of high-grade dysplasia and invasive carcinoma in mixed-type intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 2013; 13:583-8. [PMID: 24280573 DOI: 10.1016/j.pan.2013.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 08/20/2013] [Accepted: 08/21/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Morphological types and mucin protein expressions classify intraductal papillary mucinous neoplasms (IPMNs). Main duct (MD)-IPMN mostly consists of intestinal type (I-type), which expresses MUC2. Branch duct (BD)-IPMN mostly consists of gastric type (G-type), which does not express MUC2. However, the definition of mixed-type IPMN has yet to be clarified and it contains various histological types. The aim of this study was to investigate the relationship between MUC2 expression and the presence of high-grade dysplasia (HGD) and invasive carcinoma, especially in mixed-type IPMN. METHODS This retrospective study included 101 consecutive patients with surgically resected IPMNs between April 2001 and October 2012. All patients were morphologically classified into four distinct types (I-type, G-type, PB-type: pancreatobilliary, O-type: oncocytic) and immunohistochemical reactivity of various anti-mucin antibodies were investigated. RESULTS According to the classification of the 2012 international guidelines, the numbers (and histomorphological types: I/G/PB/O) of MD, mixed-type, and BD-IPMNs were 16 (12/4/0/0), 45 (16/28/1/0), and 40 (0/38/1/1). Prevalence of MUC2 expression in MD, mixed-type, and BD-IPMNs were 75% (12/16), 36% (16/45), and 0% (0/40). In mixed-type IPMN, the prevalence of HGD and/or invasive carcinoma in MUC2-positive IPMN was significantly higher than that of MUC2-negative IPMN (HGD + invasive carcinoma: 88% vs. 38%, p = 0.0017; invasive carcinoma: 50% vs. 21%, p = 0.042). Multivariate analysis showed that MUC2 expression is an independent predictive factor of HGD and invasive carcinoma in mixed IPMN (odds ratio 14.6, 95% CI 2.5-87.4, p = 0.003). CONCLUSIONS In mixed-type IPMN, MUC2 expression clearly identified HGD and invasive carcinoma and may provide most appropriate surgical indication.
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Affiliation(s)
- Atsuhiro Masuda
- Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
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Preoperative Histological Subtype Classification of Intraductal Papillary Mucinous Neoplasms (IPMN) by Pancreatic Juice Cytology With MUC Stain. Ann Surg 2013; 257:1103-11. [DOI: 10.1097/sla.0b013e318281b824] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Chakraborty S, Jain M, Sasson AR, Batra SK. MUC4 as a diagnostic marker in cancer. ACTA ACUST UNITED AC 2013; 2:891-910. [PMID: 23495864 DOI: 10.1517/17530059.2.8.891] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Mucins are high molecular mass glycoproteins whose role in diagnosis, prognosis and therapy is being increasingly recognized owing to their altered expression in a variety of carcinomas. MUC4, a membrane-bound mucin encoded by a gene located on chromosome locus 3q29, is aberrantly expressed in several cancers including those of the bile duct, breast, colon, esophagus, ovary, lung, prostate, stomach and pancreas. OBJECTIVE This review considers the potential use of the MUC4 expression pattern in the diagnosis and prognosis of various cancers. RESULTS/CONCLUSION MUC4 expression is a specific marker of epithelial tumors and its expression correlates positively with the degree of differentiation in several cancers. Importantly, MUC4 has emerged as a specific marker of dysplasia, being expressed in the earliest dysplastic lesions preceding several malignancies, including lethal pancreatic cancer. The presence of MUC4-specific antibodies in the serum and of the transcript in peripheral blood mononuclear cells of cancer patients raises the possibility of it emerging as a new diagnostic biomarker for bedside application in high-risk individuals and those with established cancer.
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Affiliation(s)
- Subhankar Chakraborty
- University of Nebraska Medical Center, Eppley Institute for Research in Cancer, Department of Biochemistry and Molecular Biology, 984525 Nebraska Medical Center, Omaha, NE 68198-5870, USA +1 402 559 5455 ; +1 402 559 6650 ;
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Lee HK, Cho MS, Kim TH. Prognostic significance of muc4 expression in gallbladder carcinoma. World J Surg Oncol 2012; 10:224. [PMID: 23101681 PMCID: PMC3500712 DOI: 10.1186/1477-7819-10-224] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2012] [Accepted: 10/15/2012] [Indexed: 12/15/2022] Open
Abstract
Background Mucins are high molecular glycoproteins and play protective and lubricating roles in various epithelial tissues. Deregulated expression of mucins is involved in carcinogenesis and tumor invasion. MUC4 expression has been identified as a poor prognostic factor in pancreatobiliary carcinomas. To date, the relation between MUC4 expression and prognosis in gallbladder carcinoma remains to be determined. Authors examined MUC4 expression in gallbladder carcinoma and investigated its impact on prognosis. Methods The expression profiles of MUC4, MUC1, MUC2 mucins in gallbladder carcinoma tissues from 63 patients were investigated using immunohistochemical staining. Results For gallbladder carcinoma, positive staining of MUC4, MUC1, and MUC2 was 55.6%, 81.0%, 28.6%, respectively. There was a significant correlation between the expression of MUC4 and the expression of MUC1 or MUC2 (p = 0.004, p = 0.009, respectively). Univariate analysis showed that MUC4 expression (p = 0.047), differentiation (p < 0.05), T-stage (p < 0.05) and lymph node metastasis (p < 0.001) were significantly associated with poor survival. Expression of MUC1 and MUC2 was not correlated to survival. The backward stepwise multivariate analysis showed that MUC4 expression (p = 0.039) and lymph node metastasis (p = 0.001) were significant independent risk factors. In combined assessment of MUC4 and MUC2 expression, MUC4 positive and MUC2 negative group showed a significantly worse outcome than MUC4 negative groups(MUC4-/MUC2+ and MUC4-/MUC2-) and MUC4/MUC2 co-expression group(MUC4+/MUC2+) (p < 0.05). Conclusions MUC4 expression in gallbladder carcinoma is an independent poor prognostic factor. Therefore, MUC4 expression may be a useful marker to predict the outcome of patients with surgically resected gallbladder carcinoma. MUC2 expression may have prognostic value when combined with MUC4 expression.
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Affiliation(s)
- Hyeon Kook Lee
- Department of Surgery, School of Medicine Ewha Womans University, 911-1 Mok-dong, Yangcheon-gu, Seoul, 158-710 South Korea.
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Evaluation of pancreatic intraepithelial neoplasia and mucin expression in normal pancreata. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2012; 19:242-8. [PMID: 21644061 DOI: 10.1007/s00534-011-0401-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/PURPOSE It has been suggested that pancreatic ductal adenocarcinoma (PDAC) and pancreatic intraepithelial neoplasia (PanIN) are closely related, but several reports indicate PanIN lesions can also be found in normal pancreata (normal PanINs). We examined differences in mucin expression between normal PanIN lesions and PanINs in PDACs (PDAC PanINs). METHODS We examined 54 autopsied normal pancreata and eight autopsied PDACs for PanIN lesions; graded the pancreata specimens as PanIN-1A (non-papillary hyperplasia), PanIN-1B (papillary hyperplasia), PanIN-2 (atypical hyperplasia) or PanIN-3 (carcinoma in situ); and tested the PanIN lesions for expression of MUC1 (pan-epithelial membrane-associated mucin) and MUC5AC (gastric secretory mucin) which were both previously detected in PDACs. RESULTS In normal PanIN-1A, PanIN-1B and PanIN-2 specimens, MUC1 was expressed in 2.8, 10.5 and 9.1%, respectively, compared to 19.1, 27.6 and 13.0% in PDAC PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively. MUC5AC was expressed in 41.0, 65.7 and 36.4% of normal PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively, and in 80.9, 75.8 and 78.3% of PDAC PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively. Differences in the frequency of MUC1 expression were significant between normal and PDAC PanIN-1A (p < 0.0001) and PanIN-1B (p < 0.05); and differences in the frequency of MUC5AC expression were significant between normal and PDAC PanIN-1A (p < 0.0001) and PanIN-2 (p < 0.05). CONCLUSIONS Normal PanIN and PDAC PanIN lesions differed in the rates of MUC1 and MUC5AC expression.
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Yonezawa S, Higashi M, Yamada N, Yokoyama S, Kitamoto S, Kitajima S, Goto M. Mucins in human neoplasms: clinical pathology, gene expression and diagnostic application. Pathol Int 2011; 61:697-716. [PMID: 22126377 DOI: 10.1111/j.1440-1827.2011.02734.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. Our immunohistochemical studies demonstrated that MUC1 or MUC4 expression is related to the aggressive behavior and poor outcome of human neoplasms. MUC2 is expressed in indolent pancreatobiliary neoplasms, but these tumors sometimes show invasive growth with MUC1 expression in invasive areas. MUC5AC shows de novo high expression in many types of precancerous lesions of pancreatobiliary cancers and is an effective marker for early detection of the neoplasms. The combination of MUC1, MUC2, MUC4 and MUC5AC expression may be useful for early detection and evaluation of the potential for malignancy of pancreatobiliary neoplasms. Regarding the mechanism of mucin expression, we have recently reported that expression of the mucin genes is regulated epigenetically in cancer cell lines, using quantitative MassARRAY analysis, methylation-specific polymerase chain reaction analysis and chromatin immunoprecipitation analysis, with confirmation by the treatment with 5-aza-2'-deoxycytidine and trichostatin A. We have also developed a monoclonal antibody against the MUC1 cytoplasmic tail domain, which has many biological roles. Based on all of the above findings, we suggest that translational research into mucin gene expression mechanisms, including epigenetics, may provide new tools for early and accurate detection of human neoplasms.
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Affiliation(s)
- Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
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MUC6 mucin expression inhibits tumor cell invasion. Exp Cell Res 2011; 317:2408-19. [PMID: 21851820 DOI: 10.1016/j.yexcr.2011.07.021] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 07/23/2011] [Accepted: 07/23/2011] [Indexed: 11/20/2022]
Abstract
The MUC6 mucin has a critical protective function in the normal stomach, pancreas and duodenum and is aberrantly expressed during the progression of some gastrointestinal cancers. Our aim was to determine whether MUC6 contributes to the etiology or progression of pancreatic cancer and elucidate the molecular basis of its involvement. Expression of MUC6 glycoprotein was examined in pancreatic cancer tissues by immunofluorescence and loss of MUC6 was observed. Next, to determine whether MUC6 inhibits tumor growth and metastasis by altering cell adhesion and invasion, recombinant MUC6 cDNA and separate MUC6 N-terminal and C-terminal domains were transfected into pancreatic, colorectal and breast cancer cell lines. The recombinant N- and C-terminal proteins were each seen to oligomerize under non-reducing conditions. Overexpression of both domains of the MUC6 glycoprotein significantly inhibited cell adhesion to matrix proteins (collagen I, collagen IV, fibronectin and laminin) in LS 180 but not in PANC-1 cells. Moreover, the N- and C-terminal domains of MUC6 inhibited invasion of both LS 180 and PANC-1 cells by 40% and 70%, respectively, in comparison with controls. These results suggest that MUC6 may inhibit invasion of tumor cells through the basement membrane of the pancreatic duct and slow the development of infiltrating carcinoma.
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Carrara S, Cangi MG, Arcidiacono PG, Perri F, Petrone MC, Mezzi G, Boemo C, Talarico A, Cin ED, Grassini G, Doglioni C, Testoni PA. Mucin expression pattern in pancreatic diseases: findings from EUS-guided fine-needle aspiration biopsies. Am J Gastroenterol 2011; 106:1359-1363. [PMID: 21647207 DOI: 10.1038/ajg.2011.22] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Alterations in mucin (MUC) glycosylation and expression have been described in cancer. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can provide material for molecular biology analysis. This study assessed the feasibility of evaluating MUC expression from material obtained by EUS-FNA and studied the profile of MUC expression in benign and malignant pancreatic lesions. METHODS A total of 90 patients with solid or cystic pancreatic lesions underwent FNA. The aspirated material was used for cytological analysis and RNA extraction to assess the expression pattern of MUCs by reverse transcription-PCR with primers specific for the MUC1, MUC2, MUC3, MUC4, MUC5A, MUC5B, MUC6, and MUC7 genes. RESULTS RNA extraction was successful in 81% of the biopsies. The prevalences of MUC1, MUC2, MUC4, and MUC7 in ductal adenocarcinoma were 57.7, 51.4, 18.9, and 73.0%, respectively. Fifty percent of benign lesions and neuroendocrine tumors (NETs), and 63% of intraductal papillary mucinous neoplasms (IPMNs) were positive for MUC1. Twenty-five percent of benign lesions, 86% of NETs, and 47% of IPMNs were positive for MUC2. Of NETs, 50% were positive for MUC1, and 14% were positive for MUC7. None of the benign lesions or NETs expressed MUC4. MUC7 expression was highly significant for adenocarcinoma (P=0.007) and borderline for IPMN (P=0.05). MUC7 was expressed in 37.5% of chronic pancreatitis cases. CONCLUSIONS RNA can be extracted from samples obtained under EUS-FNA. MUC7 could serve as a potential biological marker to identify malignant lesions, especially pancreatic adenocarcinoma.
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Affiliation(s)
- Silvia Carrara
- Division of Gastroenterology and Gastrointestinal Endoscopy, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
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Abstract
Pancreatic intraepithelial neoplasias (PanINs) are microscopic lesions of the pancreas. Traditionally viewed as a benign metaplasia of small ducts, evidence suggests that PanINs are neoplastic and that some PanINs progress to invasive ductal adenocarcinoma. The primary diagnostic challenge is distinguishing PanINs from other lesions, including invasive ductal adenocarcinoma, intraductal papillary mucinous neoplasm, and cancerization of benign ducts. PanINs are the most common of the pancreatic cancer precursor lesions, yet they remain poorly understood and are so small that they are almost clinically undetectable. Further study is required to define the role of PanINs in the carcinogenesis and early detection of pancreatic cancer.
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Yamada N, Kitamoto S, Yokoyama S, Hamada T, Goto M, Tsutsumida H, Higashi M, Yonezawa S. Epigenetic regulation of mucin genes in human cancers. Clin Epigenetics 2011; 2:85-96. [PMID: 22704331 PMCID: PMC3365379 DOI: 10.1007/s13148-011-0037-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 04/18/2011] [Indexed: 12/16/2022] Open
Abstract
Mucins are high molecular weight glycoproteins that play important roles in diagnostic and prognostic prediction and in carcinogenesis and tumor invasion. Regulation of expression of mucin genes has been studied extensively, and signaling pathways, transcriptional regulators, and epigenetic modification in promoter regions have been described. Detection of the epigenetic status of cancer-related mucin genes is important for early diagnosis of cancer and for monitoring of tumor behavior and response to targeted therapy. Effects of micro-RNAs on mucin gene expression have also started to emerge. In this review, we discuss the current views on epigenetic mechanisms of regulation of mucin genes (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC16, and MUC17) and the possible clinical applications of this epigenetic information.
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Intraductal papillary-mucinous neoplasms of the gastric and intestinal types may have less malignant potential than the pancreatobiliary type. Pancreas 2010; 39:604-10. [PMID: 20124938 DOI: 10.1097/mpa.0b013e3181c6947a] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are classified into 4 types--gastric, intestinal, pancreatobiliary, and oncocytic--on the basis of their morphology and immunohistochemistry. We classified IPMNs at our institute and used this classification to determine the clinicopathological features, prognosis, and malignant potential of the 4 types. METHODS Sixty-one patients with IPMN who underwent surgery between 2000 and 2007 were evaluated retrospectively. RESULTS There were 24 tumors of the gastric type, 22 intestinal, 12 pancreatobiliary, and 3 oncocytic. Patients with the intestinal or gastric type had a better prognosis than those with the pancreatobiliary type. The intestinal and pancreatobiliary types had almost the same frequencies of carcinoma, but the intestinal type tended to have a lower frequency of invasive carcinoma than the pancreatobiliary type. Patients with invasive carcinomas derived from intestinal-type IPMNs tended to have a better prognosis than those whose invasive carcinomas were derived from the pancreatobiliary type. CONCLUSIONS Intraductal papillary-mucinous neoplasm of the gastric and intestinal types may have less malignant potential than that of the pancreatobiliary type. Invasive carcinomas derived from intestinal-type IPMNs may be less invasive and slower growing than those derived from the pancreatobiliary type.
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Yonezawa S, Higashi M, Yamada N, Yokoyama S, Goto M. Significance of mucin expression in pancreatobiliary neoplasms. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2009; 17:108-24. [PMID: 19787286 DOI: 10.1007/s00534-009-0174-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2009] [Accepted: 08/10/2009] [Indexed: 12/11/2022]
Abstract
Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. We have described, for the first time, that pancreatic ductal adenocarcinomas (PDACs) with an aggressive behavior and a poor outcome expressed MUC1 (pan-epithelial membrane-associated mucin) but did not express MUC2 (intestinal-type secreted mucin), whereas intraductal papillary mucinous neoplasms (IPMNs) with indolent behavior and a favorable outcome did not express MUC1 but did express MUC2. These expression profiles of MUC1 and MUC2 related to the prognoses of the patients were also observed in biliary neoplasms such as intrahepatic cholangiocarcinoma (ICC)-mass-forming type (MF), mucin-producing bile duct tumor (MPBT), and extrahepatic bile duct carcinoma (EHBDC). We also found recently that high expression of MUC4 (tracheobronchial membrane-associated mucin) in PDACs, ICCs-MF, and EHBDCs was a new independent poor prognostic factor, although MUC4 was not expressed in normal pancreatobiliary tissue. High de novo expression of MUC5AC (gastric-type secreted mucin) was observed in many types of pancreatobiliary neoplasms, including all grades of pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN), and all types of IPMNs and MPBTs, as well as PDACs and ICCs-MF, although MUC5AC was not expressed in normal pancreatobiliary tissue. The combined status of MUC1, MUC2, MUC4, and MUC5AC expression may be useful for the early detection of pancreatobiliary neoplasms and evaluation of their malignancy. In regard to the mechanism of mucin expression, we have recently reported that MUC1, MUC2, MUC4, and MUC5AC gene expression is regulated by epigenetics (DNA methylation and histone H3 lysine 9 modification) in cancer cell lines, including PDAC cells. Translational research of mucin gene expression mechanisms, including epigenetics, in pancreatobiliary neoplasms may give us new tools for the early and accurate detection of these neoplasms.
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Affiliation(s)
- Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
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Higashi M, Goto M, Saitou M, Shimizu T, Rousseau K, Batra SK, Yonezawa S. Immunohistochemical study of mucin expression in periampullary adenomyoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2009; 17:275-83. [PMID: 19784541 DOI: 10.1007/s00534-009-0176-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Accepted: 08/25/2009] [Indexed: 12/28/2022]
Abstract
BACKGROUND/PURPOSE Benign tumors and tumor-like conditions in the ampullary area are uncommon, and there are extremely rare cases of adenomyoma (AM) and adenomyomatous hyperplasia (AMH). Surgical treatment is necessary if these lesions cause biliary obstruction. In addition, the differential diagnosis of AM and AMH from carcinoma is often difficult by standard endoscopic biopsy and cytopathological analysis that may show differential findings, resulting in unnecessary surgeries sometimes being performed. METHODS Immunohistochemical (IHC) analysis of periampullary AM and AMH was performed. RESULTS For both types of lesions, epithelial glandular cells (EGCs) showed diffuse expression of MUC6 and focal expression of HIK1083, mainly in the inner region, and focal expression of MUC5AC, mainly at the surface. The EGCs showed no expression of MUC1 or MUC4, both of which were identified as malignant tumor markers in our previous series of mucin expression studies in pancreatobiliary tumors. The expression of CK7, which was diffusely positive in normal periampullary mucosa, was decreased in the EGCs of AM and AMH. CONCLUSIONS A combined evaluation of IHC findings may be effective in the detection of AM and AMH, and also in distinguishing benign periampullary lesions, such as AM and AMH, from ampulla of Vater adenocarcinoma, thus avoiding excessive surgery.
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Affiliation(s)
- Michiyo Higashi
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
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Yonezawa S, Higashi M, Yamada N, Goto M. Precursor lesions of pancreatic cancer. Gut Liver 2008; 2:137-54. [PMID: 20485640 DOI: 10.5009/gnl.2008.2.3.137] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Accepted: 09/23/2008] [Indexed: 12/19/2022] Open
Abstract
This review article describes morphological aspects, gene abnormalities, and mucin expression profiles in precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN) of the pancreas, as well as their relation to pancreatic ductal adenocarcinoma (PDAC). The gene abnormalities in precursors of PDAC are summarized as follows: (1) KRAS mutation and p16/CDKN2A inactivation are early events whose frequencies increase with the dysplasia grade in both PanIN and IPMN; (2) TP53 mutation and SMAD4/DPC4 inactivation are late events observed in PanIN3 or carcinomatous change of IPMN in both PanIN and IPMN, although the frequency of the TP53 mutation is lower in IPMN than in PDAC; and (3) also in MCN, KRAS mutation is an early event whose frequency increases with the dysplasia grade, whereas TP53 mutation and SMAD4/DPC4 inactivation are evident only in the carcinoma. The mucin expression profiles in precursors of PDAC are summarized as follows: (1) MUC1 expression increases with the PanIN grade, and is high in PDAC; (2) the expression pattern of MUC2 differs markedly between the major subtypes of IPMN with different malignancy potentials (i.e., IPMN-intestinal type with MUC2+ expression and IPMN-gastric type with MUC2- expression); (3) MUC2 is not expressed in any grade of PanINs, which is useful for differentiating PanIN from intestinal-type IPMN; (4) de novo expression of MUC4, which appears to increase with the dysplasia grade; and (5) high de novo expression of MUC5AC in all grades of PanINs, all types of IPMN, MCN, and PDAC.
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Affiliation(s)
- Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
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Yonezawa S, Goto M, Yamada N, Higashi M, Nomoto M. Expression profiles of MUC1, MUC2, and MUC4 mucins in human neoplasms and their relationship with biological behavior. Proteomics 2008; 8:3329-41. [PMID: 18651706 DOI: 10.1002/pmic.200800040] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis or tumor invasion. To clarify the relationship of the expression patterns of mucins in human neoplasms with their biological behavior, we examined the expression profiles of MUC1, MUC2, and MUC4 mucins in various human neoplasms using immunohistochemistry and in situ hybridization, and compared them with clinicopathologic factors including outcome of the patients. MUC1 or MUC4 expression is related with the aggressive behavior of human neoplasms and a poor outcome of the patients. In contrast, MUC2 expression tends to be related with the indolent behavior of human neoplasms and a favorable outcome of the patients, although indolent pancreatobiliary neoplasms sometimes show invasive growth with MUC1 expression in the invasive areas. The expression of MUC2 mucin in indolent pancreatobiliary neoplasms coincided with expression of MUC2 mRNA. Our recent studies to clarify the MUC2 gene regulation mechanism disclosed that DNA methylation and histone modification in the 5' flanking region of the MUC2 promoter may play an important role. Further studies of the epigenetics also in MUC1 and MUC4 gene expression may be needed to understand the relationship between the expression of mucins in human neoplasms with their biological behavior.
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Affiliation(s)
- Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
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Nagata K, Horinouchi M, Saitou M, Higashi M, Nomoto M, Goto M, Yonezawa S. Mucin expression profile in pancreatic cancer and the precursor lesions. ACTA ACUST UNITED AC 2007; 14:243-54. [PMID: 17520199 DOI: 10.1007/s00534-006-1169-2] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Accepted: 04/11/2006] [Indexed: 12/17/2022]
Abstract
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.
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Affiliation(s)
- Kohji Nagata
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Sasaki M, Ikeda H, Nakanuma Y. Expression profiles of MUC mucins and trefoil factor family (TFF) peptides in the intrahepatic biliary system: physiological distribution and pathological significance. ACTA ACUST UNITED AC 2007; 42:61-110. [PMID: 17616258 DOI: 10.1016/j.proghi.2007.02.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mucin secreted by mucosal epithelial cells plays a role in the protection of the mucosal surface and also is involved in pathological processes. So far, MUC1-4, 5AC, 5B, 6-8, 11-13 and 15-17 genes coding the backbone mucin core protein have been identified in humans. Their diverse physiological distribution and pathological alterations have been reported. Trefoil factor family (TFF) peptides are mucin-associated molecules co-expressed with MUC mucins and involved in the maintenance of mucosal barrier and the biological behavior of epithelial and carcinoma cells. Intrahepatic biliary system is a route linking the bile canaliculi and the extrahepatic bile duct for the excretion of bile synthesized by hepatocytes. Biliary epithelial cells line in the intrahepatic biliary system, secreting mucin and other molecules involved in the maintenance and regulation of the system. In this review, the latest information regarding properties, expression profiles and regulation of MUC mucins and TFF peptides in the intrahepatic biliary system is summarized. In particular, we focus on the expression profiles and their significance of MUC mucins in developmental and normal livers, various hepatobiliary diseases and intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Takaramachi 13-1, Kanazawa 920-8640, Japan.
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Hibi Y, Fukushima N, Tsuchida A, Sofuni A, Itoi T, Moriyasu F, Mukai K, Aoki T. Pancreatic juice cytology and subclassification of intraductal papillary mucinous neoplasms of the pancreas. Pancreas 2007; 34:197-204. [PMID: 17312458 DOI: 10.1097/mpa.0b013e31802dea0] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Histological subclassification of intraductal papillary mucinous neoplasms (IPMNs) is important because the malignant potential of each subtype is different. We investigated whether pancreatic juice cytology can be used to define the subtypes of IPMNs preoperatively. METHODS The cytological findings and pathological parameters in 19 cases of IPMN were analyzed for correlations. Pancreatic juice cytology specimens were reviewed and classified into 4 types according to the criteria previously described for histological diagnosis: intestinal (Int), gastric foveolar (GF), oncocytic (Onc), and pancreatobiliary (PB), and the resected IPMNs were classified histologically using the same criteria for comparison. Immunochemical testing for MUC proteins was also performed. RESULTS In 15 cases (79%), the cytological and histological subclassifications were in agreement. The cytology specimens displayed different features corresponded to their histological subtypes. The sensitivities of the cytological diagnosis of each subtype were 80.0% (Int), 72.7% (GF), and 100% (Onc/PB); and the specificities were 85.7% (Int), 87.5% (GF), and 93.8% (Onc/PB). The cytoplasm of the Int-type cells in the pancreatic juice cytology specimens was positive for MUC2. CONCLUSIONS Most of the cytological findings of IPMNs corresponded to the histological findings. The use of MUC2 immunocytochemistry in IPMN subtyping was also demonstrated. Subtyping of IPMNs is useful for preoperative evaluation in addition to cytomorphological grading.
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MESH Headings
- Adenocarcinoma, Mucinous/classification
- Adenocarcinoma, Mucinous/mortality
- Adenocarcinoma, Mucinous/pathology
- Adenocarcinoma, Mucinous/surgery
- Adenoma/classification
- Adenoma/mortality
- Adenoma/pathology
- Adenoma/surgery
- Aged
- Carcinoma, Pancreatic Ductal/classification
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Carcinoma, Papillary/classification
- Carcinoma, Papillary/mortality
- Carcinoma, Papillary/pathology
- Carcinoma, Papillary/surgery
- Female
- Follow-Up Studies
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Mucins/metabolism
- Pancreas, Exocrine/metabolism
- Pancreas, Exocrine/pathology
- Pancreatic Ducts/metabolism
- Pancreatic Ducts/pathology
- Pancreatic Juice/cytology
- Pancreatic Neoplasms/classification
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/surgery
- Preoperative Care
- Prognosis
- Sensitivity and Specificity
- Survival Rate
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Affiliation(s)
- Yasuhiro Hibi
- The Third Department of Surgery, Tokyo Medical University, Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan
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Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS, Longnecker DS, Lüttges J, Offerhaus GJA, Shimizu M, Sunamura M, Suriawinata A, Takaori K, Yonezawa S. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch 2005; 447:794-9. [PMID: 16088402 DOI: 10.1007/s00428-005-0039-7] [Citation(s) in RCA: 472] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2005] [Accepted: 06/24/2005] [Indexed: 12/16/2022]
Abstract
Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.
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MESH Headings
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/classification
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cystadenocarcinoma, Mucinous/classification
- Cystadenocarcinoma, Mucinous/metabolism
- Cystadenocarcinoma, Mucinous/pathology
- Cystadenocarcinoma, Papillary/classification
- Cystadenocarcinoma, Papillary/metabolism
- Cystadenocarcinoma, Papillary/pathology
- Fluorescent Antibody Technique, Indirect
- Humans
- Immunoenzyme Techniques
- Mucins/metabolism
- Pancreatic Neoplasms/classification
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
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Affiliation(s)
- Toru Furukawa
- Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryomachi, Sendai, 980-8575, Japan.
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Goto M, Shibahara H, Tamada S, Hamada T, Oda K, Nagino M, Nagasaka T, Imai K, Nimura Y, Yonezawa S. Aberrant expression of pyloric gland-type mucin in mucin-producing bile duct carcinomas: A clear difference between the core peptide and the carbohydrate moiety. Pathol Int 2005; 55:464-70. [PMID: 15998373 DOI: 10.1111/j.1440-1827.2005.01854.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The authors have recently defined the clinopathological entity of a mucin-producing bile duct tumor (MPBT), and divided MPBT into two distinct subtypes: 'columnar-type' and 'cuboidal-type' MPBT. Mucin core protein 6 (MUC6), which is present in normal pyloric glands, had higher expression levels in cuboidal-type tumors than in columnar-type tumors. In the pyloric glands, a carbohydrate antigen detected by monoclonal antibody HIK1083 (CA/HIK1083) is also expressed. In order to evaluate the coexpression pattern of MUC6 and CA/HIK1083 in MPBT, expression profiles were evaluated in 38 surgically excised mucin-producing bile duct carcinomas (MPBC; cuboidal-type, n = 15; columnar-type, n = 23), using immunohistochemistry. The staining rate was graded as follows: -, <5% of neoplastic cells stained; +, 5% to <20%; + +, 20% to <50%; + + +, > or =50%. In cuboidal-type MPBC, MUC6 was positive in all cases (+ + +, 13/15; + +, 1/15; +, 1/15), whereas CA/HIK1083 was negative in all cases (-, 15/15; P < 0.0001). In columnar-type MPBC, MUC6 was positive in 65% of cases (+ + +, 6/23; + +, 8/23; +, 1/23; -, 8/23), and CA/HIK1083 was positive in 52% (+ +, 3/23; +, 9/23; -, 11/23; not significant). Our results clearly demonstrate that cuboidal-type MPBC have an aberrant pyloric glandular phenotype, that is, MUC6+/CA/HIK1083-. This unique profile may be related to different outcomes of patients with MPBC.
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MESH Headings
- Adenocarcinoma, Mucinous/metabolism
- Adenocarcinoma, Mucinous/pathology
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal/analysis
- Antigens, Tumor-Associated, Carbohydrate/biosynthesis
- Antigens, Tumor-Associated, Carbohydrate/immunology
- Bile Duct Neoplasms/metabolism
- Bile Duct Neoplasms/pathology
- Bile Ducts, Extrahepatic/chemistry
- Bile Ducts, Extrahepatic/pathology
- Carbohydrates/analysis
- Female
- Gastric Mucosa/metabolism
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Mucin-6
- Mucins/biosynthesis
- Mucins/chemistry
- Peptides/analysis
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Affiliation(s)
- Masamichi Goto
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Sasaki M, Ikeda H, Nakanuma Y. Expression Profiles of MUC Mucin Core Protein in the Intrahepatic Biliary System: Physiological Distribution and Pathological Significance. Acta Histochem Cytochem 2005. [DOI: 10.1267/ahc.38.295] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine
| | - Hiroko Ikeda
- Department of Human Pathology, Kanazawa University Graduate School of Medicine
| | - Yasuni Nakanuma
- Department of Human Pathology, Kanazawa University Graduate School of Medicine
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Su L, Hasui K, Sueyoshi K, Matsushita S, Tsuyama S, Kim BS, Kim JB, Higashi M, Yonezawa S, Murata F. Expression of Mucins in the Human Fetal and Neonatal Stomach. Acta Histochem Cytochem 2004. [DOI: 10.1267/ahc.37.163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Liying Su
- Department of Structural Cell Biology, Field of Neuro-musculoskeletal Disorder, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
- Department of Histology and Embryology, Hebei Medical University
| | - Kazuhisa Hasui
- Department of Structural Cell Biology, Field of Neuro-musculoskeletal Disorder, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
| | | | - Sachie Matsushita
- Department of Structural Cell Biology, Field of Neuro-musculoskeletal Disorder, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
| | - Shinichiro Tsuyama
- Department of Structural Cell Biology, Field of Neuro-musculoskeletal Disorder, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
| | - Bong Seon Kim
- Department of Anatomy, College of Medicine, Pusan National University
| | - Jae Bong Kim
- Department of Anatomy, College of Medicine, Pusan National University
| | - Michiyo Higashi
- Department of Human Pathology, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
| | - Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
| | - Fusayoshi Murata
- Department of Structural Cell Biology, Field of Neuro-musculoskeletal Disorder, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences
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