Intercalated duct cell is starting point in development of pancreatic ductal carcinoma?
ABSTRACT Although it is well known that the pancreatic ductal carcinoma may develop having a relationship to the mucous gland hyperplasia (MGH) with atypia (PanIN-1B by PanIN system), the starting point of this atypical MGH is unclear. To know it, we examined the pancreas tissue using many methods described below.
1. Twenty-seven surgically resected pancreas tissue specimens, including pancreatic ductal carcinomas (PDC), chronic pancreatitis and normal pancreas, were investigated using immunohistochemical stainings for MUC1, MUC6, 45M1, Ki67 and p53. 2. DNA extraction and analysis of K-ras mutation at codon 12 using microdissection method: The paraffin blocks with 16 regions including the intercalated duct cell (IC) adjacent to the atypical MGH were prepared for DNA extraction. Mutation of K-ras codon 12 was analyzed and compared in enriched polymerase chain reaction-enzyme-linked mini sequence assay (PCR-ELMA).
1. In the normal pancreas, although no positive cell was seen in 45M1, p53, Ki67, the cytoplasm of IC were always positive for MUC1 and sometimes positive for MUC6. In the pancreas with fibrosis or inflammation, MGH was positive for MUC6 and 45M1. And atypical MGH was positive for MUC1, MUC6 and 45M1. Some IC adjacent to the atypical MGH was positive for Ki67 as well as atypical MGH. The carcinoma cells in all cases of PDC were diffusely positive for MUC1, 45M1, p53 and Ki67, and focally positive for MUC6. 2. In K-ras mutation, we examined the regions including IC adjacent to the atypical MGH, because the immunohistochemical apomucin stainings of these regions resembled those of PDC as described above. And K-ras mutation was confirmed in 12 of 16 regions (75%). All mutations were a single mutation, in 6 regions GTT was detected, in 4 regions GAT was detected and in 2 region AGT was detected.
Some intercalated duct cell may be the starting point of the pancreatic ductal carcinoma, because the exhibitions of mucin expressions, Ki67, p53 and K-ras mutation in some intercalated duct cell resembled those of mucous gland hyperplasia or pancreatic ductal carcinoma.
Full-textDOI: · Available from: Ryo Wada, Sep 26, 2015
- SourceAvailable from: Yunxiao Meng
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- "Because CP is also an independent risk factor for PDAC development , high ezrin expression proportion in CP and PanINs suggests that ezrin might be involved in the earliest stages of PDAC pathogenesis and could potentially serve as an indicator for those lesions progressing to the more advanced stage--PDAC. Ezrin was also expressed in the intercalated ducts in the pancreatic tissue that was adjacent to the adenocarcinoma, which was considered to be the origin in the pancreatic ducts and acini, as well as the starting point of PDAC development [43,44]. The results indicate that ezrin may play an important role in the early development of pancreatic ductal carcinoma. "
ABSTRACT: Pancreatic cancer has a high mortality rate because it is usually diagnosed when metastasis have already occurred (microscopic and gross disease). Ezrin plays important roles in cell motility, invasion and tumor progression, and it is especially crucial for metastasis. However, its function in pancreatic cancer remains elusive. We found that ezrin overexpression promoted cell protrusion, microvillus formation, anchorage-independent growth, motility and invasion in a pancreatic cancer cell line, MiaPaCa-2, whereas ezrin silencing resulted in the opposite effects. Ezrin overexpression also increased the number of metastatic foci (6/8 vs. 1/8) in a spontaneous metastasis nude mouse model. Furthermore, ezrin overexpression activated Erk1/2 in MiaPaCa-2 cells, which might be partially related to the alteration of cell morphology and invasion. Immunohistochemical analysis showed that ezrin was overexpressed in pancreatic ductal adenocarcinoma (PDAC) (91.4%) and precancerous lesions, i.e. the tubular complexes in chronic pancreatitis (CP) and pancreatic intraepithelial neoplasm (PanIN) (85.7% and 97.1%, respectively), compared to normal pancreatic tissues (0%). Ezrin was also expressed in intercalated ducts adjacent to the adenocarcinoma, which has been considered to be the origin of ducts and acini, as well as the starting point of pancreatic ductal carcinoma development. We propose that ezrin might play functional roles in modulating morphology, growth, motility and invasion of pancreatic cancer cells, and that the Erk1/2 pathway may be involved in these roles. Moreover, ezrin may participate in the early events of PDAC development and may promote its progression to the advanced stage.Journal of Translational Medicine 06/2010; 8(1):61. DOI:10.1186/1479-5876-8-61 · 3.93 Impact Factor
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ABSTRACT: The clinicopathologic features of a hitherto unrecognized cystic tumor of the pancreas are documented, and its possible relationship to a more common incidental microscopic lesion is analyzed. Six patients (3 men and 3 women) had undergone resection specifically for this cyst type. The mean age of the patients was 63 years (range 52 to 79 y) and the mean size of the tumors was 2.6 cm (median 1.5, range 0.8 to 9 cm). The cysts had variable lining ranging from attenuated, flat squamoid cells to transitional, to stratified squamous without keratinization (no granular layer). The cells forming the basal/parabasal region expressed p63 (transitional/squamous cell marker, not detected in any normal pancreas or nonsquamous neoplasia) and the surface cells were positive for MUC 1 and MUC 6 (markers present in intercalated duct cells), and negative for GLUT-1 (consistent marker of serous adenomas). The lesions appeared to be unilocular cystic dilatation of the ducts that typically contained distinctive muco-proteinaceous acidophilic acinar secretions forming concretions, confirming their communication with the acinar system, and suggesting a localized obstruction in their pathogenesis (a form of "retention" cyst). A thin fibrous wall devoid of any lymphoid tissue separated the cysts from unremarkable parenchyma. There was no evidence of pancreatitis (fibrosis or inflammation). Separately, 110 pancreata resected for various reasons were analyzed, and what seems to be microscopic/incidental version of this process was identified in 10 examples (8%). These microcysts were found lying within compact acinar tissue, and appeared to be transforming from intercalated ducts, some focally connected to acinar elements, and they had abortive (nonbridging) septae with pseudo-loculated appearance, irregular contours and often showed tightly packed clusters of ducts with similar morphology described in the cases underwent resection specifically for this cyst type. In conclusion, the distinctive morphologic, immunophenotypic, and clinical characteristics of this cystic lesion warrant its classification as a separate entity. We propose to refer to it as squamoid cyst of pancreatic ducts. It seems to be a metaplastic cystic transformation beginning in the intercalated ducts. Although obstructive etiology is suspected, a specific factor or surrogate evidence of obstruction such as chronic pancreatitis is typically lacking.American Journal of Surgical Pathology 03/2007; 31(2):291-7. DOI:10.1097/01.pas.0000213349.42143.ec · 5.15 Impact Factor
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ABSTRACT: Pancreatic lymphoepithelial cysts are rare benign cysts that cannot be reliably differentiated from neoplastic mucinous cysts preoperatively. Although elevated cyst fluid carcinoembryonic antigen (CEA) levels support a diagnosis of a mucinous cyst, the finding of increased CEA levels in lymphoepithelial cysts prompted this study. Nine resected lymphoepithelial cysts were examined for expression of CEA, carbohydrate antigen (CA) 19-9, CK7, p63, PAS-D and a panel of mucins. The pathology data were correlated with clinical information, including serum, cyst fluid and imaging studies. By computed tomography scan, although most lymphoepithelial cysts appeared cystic, 23% were described as masses. The endoscopic ultrasound findings were variable, but the lymphoepithelial cysts tended to be hypoechoic cystic lesions or masses. On cytology, 44% of the cysts had squamous cells, 67% had glandular cells and 56% had atypical cells. The cysts were resected because of size ≥3 cm (89%), symptoms (44%) and/or elevated cyst fluid CEA levels (33%). The cyst fluid CEA levels in the three cysts tested were >450 ng/ml. Histopathologically, all cysts were lined by mature, stratified squamous-type cells and produced keratin. Mucous cells were present in 78% of the cysts. The immunohistochemical profile of the squamous lining was CK7+, p63+, MUC1+, MUC4+, MUC2-, MUC5AC- and MUC6-. Even though lymphoepithelial cysts are lined by squamous-type epithelium, all our resected lymphoepithelial cysts expressed CEA and/or CA19-9, many contained mucous cells, and three exhibited markedly elevated cyst fluid CEA levels. Although cyst fluid CEA levels >200 ng/ml support the diagnosis of mucinous neoplasms, this study emphasizes the need for clinicians and pathologists to recognize that lymphoepithelial cysts can mimic neoplastic mucinous cysts clinically, radiographically and on cyst fluid CEA analysis.Modern Pathology 11/2010; 23(11):1467-76. DOI:10.1038/modpathol.2010.144 · 6.19 Impact Factor