Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma.

PURPOSE: Nectin-1 is a cell adhesion molecule that regulates the formation of adherens junctions and tight junctions. We measured the expression of nectin-1 in cancer-associated fibroblasts (CAFs) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Nectin-1 expression was measured via immunohistochemistry using tissue microarray blocks constructed from resected PDAC tissue from 258 patients. We screened for associations between nectin-1 expression and clinicopathological parameters. According to the percentage of CAFs stained, expression was classified as negative at ≤ 30% and positive at > 30%. RESULTS: Nectin-1 expression was confirmed in CAFs from 64 patients (24.8%), and was associated with lymph node metastasis (p = 0.016), advanced Union for International Cancer Control stage (p = 0.016), perineural invasion (p = 0.022), pancreatic head tumors (p = 0.023), and shorter overall survival (p = 0.003). Multivariate analysis revealed that nectin-1 expression in CAFs was an independent prognostic factor (p = 0.038). CONCLUSIONS: Diffuse nectin-1 expression in the CAFs of PDAC patients is associated with invasion, metastasis, and shorter survival.

Epidermoid cysts are a characteristic feature of intrapancreatic but not of extrapancreatic accessory spleens.

Accessory spleens (ASs), ectopic splenic tissue at intrapancreatic and extrapancreatic sites, rarely contain epidermoid cysts. Our aim was to analyze the incidence of epidermoid cysts in ASs and perform an immunohistochemical analysis of its epithelial lining. We included in the study 148 ASs from 135 patients, for which pathological data were available. Eleven were intrapancreatic ASs (IPASs) and 137 were extrapancreatic ASs (EPASs). Six of the eleven (55%) IPASs contained epidermoid cysts, but they were not detected in EPASs. Immunohistochemical analysis showed that both the superficial/luminal and basal layer of the epithelial lining of epidermoid cysts in IPASs are negative for MUC2, MUC5AC, MUC6, WT-1, calretinin, thrombomodulin, uroplakin-II, and uroplakin-III. The superficial/luminal layer was positive for MUC4, CK7, and CA19-9 in all cases (100%), for CEA and HBME-1 in three cases (50%), and for MUC1, CK5/6, and CK20 in two cases (33%). The superficial/luminal layer was negative for p63 and D2-40 in all cases. The basal layer was positive for MUC1, CK5/6, p63, and HBME-1 in all six cases (100%), for CK7 and D2-40 in two cases (33%), and for CEA in one case (17%). The basal layer was negative for MUC4, CK20, and CA19-9 in all cases. Epidermoid cysts are a characteristic feature of IPASs but not of EPASs. Immunohistochemical analysis showed that the epithelial lining of epidermoid cysts in IPASs has a mixed character of glandular, squamous, mesothelial, and urothelial epithelium.

A Serous Cystic Neoplasm of the Pancreas Coexisting with High-Grade Pancreatic Intraepithelial Neoplasia Mimicking an Intraepithelial Papillary Mucinous Neoplasm: A Case Report.

Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.

Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma.

AIMS: The loss, or decreased expression, of nectin-like molecule 4 (Necl-4; an immunoglobulin-like cell adhesion molecule) is reported to be associated with the development and progression of certain types of cancer. We investigated the clinicopathological significance of Necl-4 expression in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Immunohistochemical analyses of Necl-4 (n=258) and E-cadherin (n=256) expression were performed using tissue microarray blocks of PDAC samples. Necl-4 expression of 38 pancreatic intraepithelial neoplasia (PanIN) lesions included in tissue microarray cores was also evaluated. Necl-4 and E-cadherin expression was considered positive if >30% of cells were stained, and negative if ≤30% of cells were stained. RESULTS: Necl-4 expression was positive in 45.7% (n=118) and negative in 54.3% (n=140) of PDAC cases. Necl-4 staining was positive in 96.7% (n=29) and negative in 3.3% (n=1) of low-grade PanIN cases, and positive in 62.5% (n=5) and negative in 37.5% (n=3) of high-grade PanIN cases. The number of cases with positive Necl-4 expression decreased in the order low-grade PanIN>high-grade PanIN>PDAC (p<0.001). Negative Necl-4 expression was significantly associated with a larger tumour size of >30 mm, perineural invasion, lymphatic involvement, lymph node metastasis (pN1), an advanced TNM (tumour, node, metastases) stage (stage IIB-IV), an advanced histological grade (G2/3), and shorter overall survival. E-cadherin staining was positive in 46.1% (n=118) and negative in 53.9% (n=138) of PDAC cases. Necl-4 expression correlated positively with E-cadherin expression (r=0.405, p<0.001). CONCLUSIONS: The results suggest that Necl-4 is associated with carcinogenesis and aggressiveness of PDAC.

Bone morphogenetic protein-2 expression in an intraductal papillary mucinous neoplasm with marked ossification: A case report.

Intratumoral ossification has been reported in a number of epithelial tumors, but its presence in intraductal papillary mucinous neoplasms (IPMNs) is very rare. Herein, we present a rare case of IPMN with marked ossification. A 56-year-old Japanese man was under follow-up for a previously diagnosed IPMN. Seven years later, he was found to have dilatation of the main pancreatic duct and an enlarged solid mass, for which pancreaticoduodenectomy was performed. Macroscopically, multiple and cystically dilated pancreatic branch ducts, as well as a dilated main pancreatic duct, were identified. There was a solid, polypoid hard mass measuring 15 × 12 mm in the cystically dilated branch of the duct in the pancreatic head. Histological examination revealed papillary proliferation of atypical cuboidal or columnar epithelial cells in the dilated main and branch pancreatic ducts. The solid mass included an invasive adenocarcinoma component with a tubular or trabecular structure that showed pronounced ossification. We diagnosed the patient with invasive IPMN accompanied by marked ossification. Immunohistochemically, tumor cells in both the non-invasive and invasive lesions expressed bone morphogenetic protein-2 (BMP-2). While the mechanism of intratumoral ossification is unclear, it may have involved BMP-2 in the present case.

Molecular alterations in sporadic pancreatic neuroendocrine microadenomas.

BACKGROUND: Pancreatic neuroendocrine microadenomas (pNEMAs) are neuroendocrine tumors measuring <5 mm in diameter. They are considered the precursor of pancreatic neuroendocrine tumors (pNETs). The aim of this study was to investigate the immunohistochemical differences between pNEMA, pNET, and hyperplasia of pancreatic islet cells (HPIL) in patients with non-familial syndromes. METHODS: We evaluated 21 pNEMAs, 19 HPILs, and 21 non-functional pNETs (10 G1 and 11 G2 cases) in patients with non-familial syndromes. Immunohistochemistry for tumor-associated markers death domain-associated protein (DAXX), alpha thalassemia/mental retardation X-linked (ATRX), cytokeratin 19 (CK19), bcl-2, and CD99 was performed. RESULTS: DAXX was expressed in 95%, 71%, and 71% of HPIL, pNEMA, and pNET samples, respectively; the differences were not significant. ATRX expression in pNEMA and pNET was significantly lower than that in HPIL, whereas there was no significant difference between pNEMA and pNET (HPIL: 95%, pNEMA: 43%, and pNET: 52%). All HPIL and pNEMA cases were negative for bcl-2 and positive for CD99, whereas 29% of pNETs were positive for bcl-2 and 24% were negative for CD99. CK19 expression in HPIL was significantly lower than in pNEMA and pNET, although no significant difference was observed between pNEMA and pNET (HPIL: 5%, pNEMA: 57%, and pNET: 43%). Among G1 and G2 pNETs, CD99 was expressed in 50% of G1 pNETs but not in any G2 pNET cases. CONCLUSION: Non-familial HPIL, pNEMA, and pNET patients exhibit distinct ATRX, CD99, CK19, and bcl-2 molecular profiles.

Positive Intraoperative Peritoneal Lavage Cytology is a Negative Prognostic Factor in Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Center Study.

OBJECTIVE: The aim of this study is to evaluate the prognostic significance of intraoperative peritoneal lavage cytology (PLC) in pancreatic invasive ductal adenocarcinoma. METHODS: Intraoperative PLC was evaluated in 162 patients with resectable pancreatic invasive ductal adenocarcinoma. The results were analyzed for correlations with clinicopathological parameters and/or prognoses. RESULTS: In the 162 cases of resectable pancreatic ductal adenocarcinoma, 18 (11%), 141 (87%), and 3 (2%) were positive, negative, and equivocal for intraoperative PLC, respectively. Intraoperative PLC positivity was associated with older patients (over 65 years), large tumor size (over 35 mm), tumor location in the body/tail of the pancreas, and distant metastasis. Univariate analysis showed that larger tumor sizes (≥35 mm, P = 0.001), lymph node metastases (P = 0.005), distant metastasis (P = 0.004), advanced stage (stage IIB or III, P = 0.006), advanced tumor histological grade (G3, P < 0.001), or positive intraoperative PLC (P = 0.002) are associated with a shorter survival. Multivariate analysis revealed that larger tumor sizes (≥35 mm, P = 0.026), lymph node metastasis (P = 0.021), advanced tumor histological grade (G3, P < 0.001), and positive intraoperative PLC (P = 0.002) were independent prognostic factors. CONCLUSION: Intraoperative PLC is an independent prognostic factor for resectable pancreatic invasive ductal adenocarcinoma.