Masamichi Goto

New classification of pancreatic intraductal papillary–mucinous tumour by mucin expression: its relationship with potential for malignancy

In previous studies of the expression of MUC1 (membrane‐bound type mucin) and MUC2 (intestinal type secretory mucin) in pancreatic tumours, invasive ductal carcinoma (IDC) usually showed MUC1+ and MUC2− expression, whereas intraductal papillary–mucinous tumour (IPMT) showed MUC1− and MUC2+ expression. Recently, however, many IPMTs have been collected, a considerable number of which have shown MUC1− and MUC2− expression. In the present study, the clinicopathological features were examined of 18 IPMTs with MUC2+ and 32 IPMTs with MUC2−, and their potential for malignancy was compared. Most of the IPMTs with MUC2+ were composed of dark columnar cells, whereas most of the IPMTs with MUC2− were composed of clear columnar cells. The incidence of carcinomatous change and invasive proliferation of the carcinoma in the MUC2+ tumours was significantly higher than in the MUC2− tumours. The clinical outcome for the patients with IPMT showing the MUC2+ pattern tended to be worse than for those with IPMT showing the MUC2− pattern, although the overall outcome for the two types of IPMT was significantly better than for those with IDC. Because of the differences in mucin expression pattern, morphological appearance and potential for malignancy between the two types of IPMT, we believe that they belong to different neoplastic lineages and that it may be reasonable to classify them as different entities, although the WHO classification contains a single clinicopathological entity of IPMT forming an adenoma–carcinoma sequence. In conclusion, our classification of IPMTs by MUC2 expression pattern may be of value in the better assessment of the biological behaviour of IPMTs and their potential for malignancy. Copyright

Pathologic Features of Mucin-producing Bile Duct Tumors: Two Histopathologic Categories as Counterparts of Pancreatic Intraductal Papillary-mucinous Neoplasms

Tumors with clinically recognizable mucin production arising from bile duct, “mucin-producing bile duct tumors (MPBTs),” have not been studied yet for their pathologic features and classification in details. The clinical findings of MPBT have a lot of similarities to those of pancreatic intraductal papillary-mucinous neoplasm. In the present study, we examined 30 MPBTs and classified them into two distinct morphologic categories: 22 cases of “columnar type” composed of pseudostratified columnar cells with basophilic cytoplasm and columnar nuclei and 8 cases of “cuboidal type” composed of pancreaticobiliary and/or oncocytic pattern. Pancreaticobiliary pattern showed abundantly branched papillae lined by acidophilic cuboidal cells with round nuclei, whereas oncocytic pattern was characterized by intraepithelial lumina and cribriform pattern composed of abundant oxyphilic cells with round nuclei, and these patterns overlapped frequently. There were significant differences in the clinicopathologic findings including macroscopic findings, morphometric data, mucin expression profiles (MUC2 expression in columnar type and MUC6 expression in cuboidal type), and cell proliferative activities between columnar type and cuboidal type. Patients with columnar type showed significantly poorer survival than those with cuboidal type. We concluded that columnar type and cuboidal type of MBPTs belong to different lineage of neoplasm and that they are counterparts of “intestinal type” and “pancreaticobiliary type” of pancreatic intraductal papillary-mucinous neoplasm, respectively.

MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas

Background: Many patients with invasive ductal carcinoma of the pancreas (IDC) have a poor outcome. MUC4 expression has been implicated as a marker for diagnosis and progression of IDC, but there are no studies of the relation between MUC4 expression and patient prognosis in IDC. Aims: To investigate the prognostic significance of MUC4 expression in IDC. Methods: The expression profiles of MUC4, ErbB2, p27, and MUC1 were investigated in IDC tissues from 135 patients by means of immunohistochemistry. Results: MUC4 was expressed in 43 of the 135 patients with IDC (31.9%). The survival of 21 patients with high MUC4 expression (>20% of neoplastic cells stained) was significantly worse than that of the 114 patients with low MUC4 expression (<20% of neoplastic cells stained) (p  =  0.0043). Univariate analysis showed that high MUC4 expression (p  =  0.0061), large primary tumour status (>T2) (p  =  0.0436), distant metastasis (p  =  0.0383), lymphatic invasion (p  =  0.0243), and surgical margins (p  =  0.0333) were significant risk factors affecting the outcome of patients with IDC. Backward stepwise multivariate analysis showed that MUC4 expression (p  =  0.0121), lymph node metastasis (p  =  0.0245), and lymphatic invasion (p  =  0.0239) were significant independent risk factors. ErbB2, p27, and MUC1 were not independent risk factors. Conclusions: This study shows that MUC4 expression in IDC is a new independent factor for poor prognosis and predicts the outcome of patients with IDC.

MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type

Complete surgical resection of the tumor is the sole approach to improve the cure rate of patients with intrahepatic cholangiocarcinoma‐mass forming type (ICC‐MF). Although patients are treated by curative resection, many of them show poor outcome. Mucin (MUC)4 expression has been implicated as a marker for diagnosis and progression of pancreatic adenocarcinomas, but there is no study of the relationship between MUC4 expression and patients prognosis in ICC‐MF. In the present study, we examined the expression profile of MUC4 in ICC‐MF tissue from 27 patients using immunohistochemistry. MUC4 was expressed in the carcinoma tissues of 10 (37%) of the 27 ICC‐MF tumors, whereas it was not expressed in normal liver tissue. Because MUC4 is an intramembrane ligand for receptor tyrosine kinase ErbB2 and is related with regulation of p27, we also compared the MUC4 expression with ErbB2 and p27 expressions in ICC‐MFs. The patients with MUC4 and ErbB2 double positive expression showed a short survival period compared to non‐expressing patients. MUC4 and p27 showed no relationship. The univariate analysis showed that tumor size, intrahepatic metastasis, lymph node metastasis, MUC4 expression, and MUC1 expression were statistically significant risk factors affecting the outcome of the patients with ICC‐MF. The multivariate analysis demonstrated that MUC4 expression, as well as surgical margin, were statistically significant independent risk factors. In conclusion, the results suggest that expression of MUC4 in ICC‐MF is a new independent factor for poor prognosis and is a useful marker to predict the outcome of the patients with ICC‐MF. (HEPATOLOGY 2004;39:220–229.)

Expression profiles of MUC1, MUC2, and MUC4 mucins in human neoplasms and their relationship with biological behavior.

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.

Midkine is present in the early stage of cerebral infarct

Expression of midkine (MK), a growth factor with neurotrophic activities, was examined immunohistochemically in experimental cerebral infarct of rats. From postoperative day 1 to day 7 after the onset of infarct, anti-MK immunoreactivity was observed in the surrounding ischemic zone of the infarct but not in the necrotic lesion. The immunoreactive material was identified to be MK by Western blotting. On day 14, anti-MK immunoreactivity became negative. Absence of MK in the normal brain was verified both by immunohistochemical staining and Western blotting. The induced expression of MK is an early event: increased expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, started on day 4 and continued to day 14. These findings suggest that MK is produced around the site of nerve damage and plays a role as a reparative neurotrophic factor during the early phase of cerebral infarct.

Significance of mucin expression in pancreatobiliary neoplasms

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.

Are nonfunctioning pituitary adenomas extending into the cavernous sinus aggressive and/or invasive?

OBJECTIVEWe studied nonfunctioning pituitary adenomas extending to the cavernous sinus to gain insight into the discrepancy between their histologically benign nature and frequent extension into the cavernous sinus. METHODSWe studied 10 patients with nonfunctioning pituitary adenomas that completely encircled the cavernous carotid artery (extension group). All 10 patients underwent surgery to remove intrasellar and/or suprasellar parts of the adenomas. Ten patients with nonfunctioning pituitary adenomas without cavernous sinus extension comprised the control group. Tumor size follow-up data were obtained by magnetic resonance imaging. Immunostaining was performed for Ki-67, cathepsin B, and matrix metalloprotainase-9. To assess the wall thickness, 10 cavernous sinuses were removed from the cranial base of adult cadavers, and the walls were examined histologically. RESULTSMagnetic resonance imaging demonstrated no remarkable growth in most of the patients during the follow-up period (mean, 65.8 mo). There was no statistical difference in Ki-67, cathepsin B, and matrix metalloprotainase-9 immunostaining between the extension group and the control group. The cadaver study demonstrated that the medial wall was significantly thinner than the superior and the lateral walls (P < 0.0005). We found small defects in the capsule histologically in 3 of 30 sections. CONCLUSIONOur results indicate that most of nonfunctioning pituitary adenomas extending into the cavernous sinus are neither aggressive nor invasive. The high incidence of cavernous sinus extension of benign adenomas may be caused by the weakness of the medial wall of the cavernous sinus.

Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in mucinous carcinoma of the breast: comparison with invasive ductal carcinoma

Aims:  Mucinous carcinoma of the breast usually shows less frequent lymph node metastasis and more favourable outcome compared with invasive ductal carcinoma. The aim of this study is to compare the expression profiles of several mucins in mucinous carcinomas and invasive ductal carcinomas to gain insight into the relationship between the less aggressive biological nature of mucinous carcinoma and the role of mucins.

Expression of MUC1 and MUC2 mucins in extrahepatic bile duct carcinomas: Its relationship with tumor progression and prognosis

Our previous immunohistochemical studies in the pancreas, intrahepatic bile duct, and ampulla of Vater demonstrated that an invasive carcinoma with a poor outcome showed a pattern of MUC1 (membrane‐bound mucin) positive and MUC2 (intestinal‐type secretory mucin) negative, whereas many of the non‐invasive tumors with favorable outcome showed a pattern of MUC1 negative and MUC2 positive. The aim of this study is to compare the expression profiles of MUC1 and MUC2 mucins in extrahepatic bile duct carcinomas to gain insight into the relationship between the biological nature of the carcinomas and the role of mucins. We examined the expression profiles of MUC1 of different glycoforms and MUC2 in 60 extrahepatic bile duct carcinomas using immunohistochemistry. The expression of MUC1/CORE (core peptide of MUC1), MUC1/DF3 (core peptide of MUC1 with sialyl oligosaccharides) and MUC1/MY.1E12 (sialylated MUC1) showed a significant relationship with tumor progression factors such as poor differentiation, deep invasion, lymph node metastasis, lymphatic invasion or perineural invasion. In contrast, the expression of MUC1/HMFG‐1 (fully glycosylated MUC1) did not show a significant relationship with the tumor progression factors. In the different glycoforms of MUC1 examined, the expression of MUC1/DF3 and MUC1/MY.1E12 was related with the poor outcome of the patients. In contrast, the expression of MUC2 was inversely related with the tumor progression factors and poor outcome. In the 52 patients with advanced tumors, only MUC1/DF3 high expression correlated with poor prognosis. In conclusion, MUC1/DF3 was the most useful prognosis indicator among the various glycoforms of MUC1 mucins.