Langerin is a type II transmembrane C-type lectin associated with the formation of Birbeck granules in Langerhans cells. Langerin is a highly selective marker for Langerhans cells and the lesional ...cells of Langerhans cell histiocytosis. Although Langerin protein expression in Langerhans cell histiocytosis has been previously documented, the specificity of Langerin expression as determined by immunohistochemistry in the context of other histiocytic disorders has not been well established. In the present study, Langerin immunoreactivity was examined in a series of histiocytic disorders of monocyte/macrophage and dendritic cell derivation to assess the specificity and utility of Langerin as a diagnostic marker for Langerhans cell histiocytosis. Immunohistochemical expression of CD1a was also evaluated for comparison. Seventeen cases of Langerhans cell histiocytosis and 64 cases of non-Langerhans cell histiocytic disorders were examined. Langerin and CD1a were uniformly expressed in all cases of Langerhans cell histiocytosis, with the exception of one case that was positive for Langerin and negative for CD1a. Among the non-Langerhans cell histiocytic disorders evaluated, focal Langerin immunoreactivity was observed only in 2 of 10 cases of histiocytic sarcoma. All non-Langerhans cell histiocytic disorders showed no expression of CD1a. Langerin expression seems to be a highly sensitive and relatively specific marker of Langerhans cell histiocytosis. Immunohistochemical evaluation of Langerin expression may have utility in substantiating a diagnosis of Langerhans cell histiocytosis and separating this disorder from other non-Langerhans cell histiocytic proliferations.
Mucinous adenocarcinomas (MAs) of various origins may have a similar histologic appearance and frequently metastasize to distant sites, which often causes diagnostic problems in surgical pathology ...practice. The immunohistochemical profiles of MAs of various origins have not been well studied. We investigated the expression of 10 immunohistochemical markers (CK7, CK20, CDX-2, β-catenin, MUC-1, MUC-2, MUC-6, ER, WT-1, and PAX-8) in 175 cases of MA, including 69 cases from the lower gastrointestinal (GI) tract, 41 from the upper GI tract, 27 from gynecologic organs, 4 from the urinary bladder, 18 from the breast, and 16 from the lung. We found that lower GI MAs (colon, rectum, and anus) frequently expressed CDX-2 (42 of 42, 100%; 33 of 42 with homogenous positivity, 79%), MUC-2 (42 of 42; 100%), CK20 (41 of 42; 98%), and β-catenin (nuclear) (27 of 42; 64%) and rarely expressed MUC-6 (2 of 42; 5%) and CK7 (8 of 42; 19%). Most of the CK7-positive cases were from the rectum and anus (7 of 8; 88%). The expression of these markers in appendiceal MAs was similar to that of low GI tract MAs, except for a lower percentage of homogenous CDX-2 (3 of 27; 11%) and nuclear β-catenin (3 of 27; 11%) expression. Unlike their lower GI tract counterparts, the upper GI tract MAs (ampulla, pancreas/biliary tree, and stomach/esophagus) frequently expressed CK7 (38 of 41; 93%) and MUC-6 (31 of 41; 76%) and were rarely homogenously positive for CDX-2 (4 of 41; 10%) and nuclear positive for β-catenin (8 of 41; 19%). Breast MAs were frequently positive for CK7 (18 of 18; 100%), MUC-1 (18 of 18; 100%), MUC-2 (18 of 18; 100%), ER (16 of 18; 89%), MUC-6 (9 of 18; 50%), and WT-1 (9 of 18; 50%). Lung MAs were frequently positive for CK7 (16 of 16; 100%) and MUC-1 (15 of 16; 94%). Gynecologic MAs were positive for CK7 (25 of 27; 93%) and PAX-8 (13 of 27; 48%). We conclude that homogenous CDX-2 and nuclear β-catenin expressions are commonly seen in lower GI tract MAs. In contrast, appendiceal MAs are usually heterogenously positive for CDX-2 and show cytoplasmic positivity for β-catenin. Unlike lower GI tract MAs, upper GI tract MAs are frequently positive for CK7 and MUC-6. As is the case in appendiceal MAs, the upper GI tract MAs may also be heterogenously positive for CDX-2. Breast MAs are positive for ER and WT-1, whereas gynecologic MAs are positive for PAX-8 and negative for WT-1.
Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI ...misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.
Immunohistochemical expression of napsin A in primary pulmonary mucinous tumors is not well established. Napsin A immunoreactivity was evaluated in 43 mucin-producing adenocarcinomas of the lung ...consisting of 18 tumors formerly classified as mucinous bronchioloalveolar carcinoma, 15 colloid adenocarcinomas, 5 solid predominant adenocarcinomas with mucin production, and 5 adenocarcinomas with signet ring cell features, as well as in 25 extrapulmonary mucinous adenocarcinomas of different anatomic sites. Immunohistochemical expression of thyroid transcription factor 1 (TTF-1) was also compared. Thirty-three percent of mucinous lung tumors exhibited positive immunoreactivity for napsin A, whereas 42% expressed TTF-1. All 25 extrapulmonary mucinous adenocarcinomas lacked expression of napsin A and TTF-1. Mucin-producing neoplasms of the lung infrequently express napsin A, suggesting that immunohistochemical assessment of napsin A may have limited diagnostic usefulness for distinguishing primary and metastatic mucinous adenocarcinomas involving the lung.
We studied the immunophenotype of signet-ring cell carcinoma (SRCC) of the stomach (30 cases), breast (21 cases), and colon (9 cases) with the following expression patterns: (1) breast: consistent, ...MUC1 (21 100%), cytokeratin (CK) 7 (20 95%), estrogen receptor (ER; 17 81%); infrequent, E-cadherin (6 29%), MUC2, MUC5AC, CK20 (1 5% each); negative, CDX2 and hepatocyte paraffin 1 (Hep Par 1; 0 0% each); (2) gastric: frequent, CDX2 (27 90%) and Hep Par 1 (25 83%); variable, E-cadherin and CK20 (17 57% each), MUC2 and MUC5AC (15 50% each), MUC1 (5 17%); negative, ER (0 0%); and (3) colon: frequent, MUC2 (9 100%), CDX2 and MUC5AC (8 89% each); infrequent or negative, MUC1 (3 33%), Hep Par 1 (2 22%), ER (0 0%). Immunohistochemical staining distinguished breast from gastric SRCC (ER, MUC1, Hep Par 1, CDX2) and colon SRCC (ER, CDX2, MUC2, and MUC5AC). Gastric and colon SRCCs showed a similar staining pattern for antibodies tested except for Hep Par 1 and CDX2 (gastric, 83% Hep Par 1 positivity and heterogeneous, weak, patchy CDX2 nuclear staining; colon, 22% Hep Par 1 positivity and homogeneous, strong, diffuse CDX2 nuclear staining). About half of the cases of gastric SRCC expressed MUC2 and MUC5AC, whereas virtually all cases of colon SRCC expressed them.
Cytokeratin 5/6 (CK 5/6) immunoreactivity has been observed in the vast majority of cases of malignant mesothelioma but only rarely in pulmonary adenocarcinomas. Thus, CK 5/6 has been used to ...distinguish malignant mesothelioma from pulmonary adenocarcinoma. However, the utility of CK 5/6 in distinguishing pleural malignant mesothelioma from pleural metastases from nonpulmonary adenocarcinoma, as well as peritoneal malignant mesothelioma from peritoneal metastatic adenocarcinoma, has not yet been adequately addressed because the tissue expression of CK 5/6 in nonpulmonary neoplasms has not been well defined. We have studied the CK 5/6 expression in 509 cases of various epithelial tumors by immunohistochemistry. We found that the vast majority of cases of squamous cell carcinoma, basal cell carcinoma, thymoma, salivary gland tumor, and biphasic malignant mesothelioma were positive for CK 5/6. In addition, CK 5/6 immunoreactivity was detected in 15 of 24 cases (62%) of transitional cell carcinoma, in 5 of 10 cases (50%) of endometrial adenocarcinoma, in about one third of cases of pancreatic adenocarcinoma (38%) and breast adenocarcinoma (31%), and in one quarter of cases of ovarian adenocarcinomas (25%). Our study confirms the diagnostic utility of CK 5/6 immunohistochemistry in distinguishing biphasic mesothelioma from pulmonary adenocarcinoma but raises caution about its use for the differential diagnosis of pleural or peritoneal malignant mesothelioma versus pleural or peritoneal metastatic nonpulmonary adenocarcinoma, because many types of nonpulmonary adenocarcinomas may be positive for CK 5/6.
Paraffin-section immunohistochemical analysis was performed using a monoclonal antibody against CD163 to evaluate the antibody's usefulness in identifying cells of monocyte/macrophage lineage in ...normal and neoplastic conditions. Normal human tissue samples and samples from 211 hematopoietic disorders and 115 nonhematopoietic neoplasms were examined. The distribution of KP1 and PG-M1, monoclonal antibodies to the macrophage-associated CD68 antigen, also were evaluated for comparison. CD163 immunoreactivity was observed in resident macrophages of all normal tissue samples except splenic white pulp macrophages and germinal center tingible body macrophages. Among hematopoietic disorders and nonhematopoietic neoplasms, CD163 expression was restricted largely to cases of chronic myelomonocytic leukemia, histiocytic sarcoma, sinus histiocytosis with massive lymphadenopathy, and littoral cell angioma. Acute myeloid leukemias (AMLs) with monocytic differentiation were CD163- with the exception of 1 case of acute monoblastic leukemia. Most myeloid sarcomas also were CD163-. Compared with the CD68 antibodies, CD163 demonstrated greater specificity as a marker of disorders of monocyte/macrophage origin. However, immunohistochemical evaluation of CD163 expression does not seem to be a sensitive means of determining monocytic differentiation in AMLs in paraffin sections or establishing a diagnosis of myeloid sarcoma.
Glypican-3 (GPC3) protein expression was determined by immunohistochemical analysis from 29 normal livers, 80 cirrhotic livers sample taken near hepatocellular carcinoma (HCC), and 87 cirrhotic ...livers without HCC. The levels for miR-657 and HCC-related gene mRNAs were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Also, a published microarray dataset was used for gene set enrichment analysis (GSEA) to investigate the relationship between GPC3- and HCC-related gene signatures. Kaplan-Meier analysis was used to evaluate the relationship between GPC3 and HCC recurrence. GPC3 protein expression was not detected in any of the 29 (0%) normal livers, but was detected in 32 of 87 (37%) cirrhotic livers without HCC, and 51 of 80 (64%) cirrhotic liver samples taken near HCC sites (P < 0.001). The GPC3-positive rate in cirrhotic livers of viral origin was 68% (27/40), which was significantly higher than for non-viral cirrhotic livers (11%, 5/47) (P < 0.001). Also, GPC3 expression positively correlated with mRNA expression of HCC-related genes in the qRT-PCR and GSEA evaluations. Furthermore, HCC recurrence in cirrhotic liver samples taken near HCC sites was significantly higher in the GPC3-positive group than the GPC3-negative group (Log-rank P = 0.02, HR = 3.26; 95% CI = 1.20-10.29). This study demonstrated that highly expression of GPC3 could enrich HCC-related genes' mRNA expression and positive associate with dysplasia in cirrhotic livers. Therefore, GPC3 may serve as a precancerous biomarker in cirrhotic livers.
Distinguishing a well-differentiated hepatocellular carcinoma (HCC) from normal and cirrhotic liver tissue or benign liver nodules, such as hepatic adenoma (HA) and focal nodular hyperplasia (FNH), ...may be very difficult in some cases, particularly in small needle core biopsies. We studied the expression of Glypican-3 (GPC3) and CD34 in 107 cases of HCC, 19 cases of HA, and 16 cases of focal nodular hyperplasia (FNH). In addition, we studied GPC3 expression in 225 cases of nonhepatic human tumors with epithelial differentiation. Ninety-four of 107 cases (88%) of HCC showed focal or diffuse cytoplasmic GPC3 staining, whereas all HA and FNH cases were GPC3-negative, and only 7 of 225 cases (3%) of nonhepatic tumors with epithelial differentiation expressed GPC3. The sensitivity and specificity of GPC3 for HCC was 88% and 97%, respectively. There were three CD34 staining patterns observed in hepatic tissue: negative, incomplete positive, and complete positive. In negative staining pattern, only blood vessels in portal triads or rare sinusoidal spaces immediately adjacent to portal tracts were positive. The negative staining pattern was seen in normal or cirrhotic liver tissue only. The complete CD34 staining pattern showed virtually all sinusoidal spaces with CD34-positive staining throughout the lesion. The complete CD34 staining pattern was seen in virtually all cases of HCC and in only some cases of HA and FNH. The incomplete CD34 staining pattern was characterized by either CD34 positivity in virtually all sinusoidal spaces in some but not all nodules or CD34 positivity in the peripheral sinusoidal spaces adjacent to portal triads. The incomplete CD34 staining pattern was seen in rare cases of HCC and in most cases of HA and FNH. We conclude that GPC3 is a very specific marker not only for differentiating HCC from nonhepatic tumors with epithelial differentiation, but also for differentiating HCC from HA and FNH. GPC3 immunoreactivity, in combination with a complete CD34 immunostaining pattern, greatly facilitates the accuracy of distinguishing between malignant hepatic lesions and benign mimickers.
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