Decreased matriptase/HAI-1 ratio in advanced colorectal adenocarcinoma of Chinese patients

Matriptase is a serine protease expressed by tumors of surface epithelial origin. We tested the expressions of matriptase and hepatocyte growth factor activator inhibitor-1 (HAI-1) maybe associated with the progression of colorectal adenocarcinoma. Immunohistochemical analysis of matriptase and HAI-1 was performed in tissue microarray slides of 91 colorectal adenocarcinomas with various degrees. The matriptase scores in moderately (346.7 +/- 10.6) and poorly differentiated (248.1 +/- 12.9) were significantly lower than those in well differentiated (368.4 +/- 9.6) colorectal adenocarcinomas. The matriptase/HAI-1 ratios in poorly (1.8 +/- 0.4) and moderately differentiated (1.8 +/- 0.3) were significantly lower than in well differentiated (2.2 +/- 0.2) colorectal adenocarcinomas. Otherwise, the matriptase scores and matriptase/HAI-1 ratio showed significant reverse correlation with more advanced TNM stages of colorectal adenocarcinomas in Chinese patients. In conclusion, pharmacological inhibitors of matriptase may not be effective treatment for advanced colorectal adenocarcinomas.     

Association of cortactin and fascin-1 expression in gastric adenocarcinoma: correlation with clinicopathological parameters.

Cortactin and fascin-1 are important factors in tumor progression. We tested the hypothesis that cortactin and fascin-1 expression correlates with clinicopathological parameters of gastric adenocarcinoma. Immunohistochemical analysis of cortactin and fascin-1 was done using tissue microarrays of 100 surgical specimens, including 20 well-differentiated, 20 moderately differentiated, and 60 poorly differentiated gastric adenocarcinomas. Among the 20 well-differentiated gastric adenocarcinomas, 15 cases (75%) showed negative or weak staining (1+); 5 cases (25%) had moderate (2+) or strong (3+) cortactin expression. Among the 60 poorly differentiated gastric adenocarcinomas, more than three-quarters of the cases (76.7%) had moderate or strong cortactin expression; 14 cases (23.3%) had weak staining. Of 20 well-differentiated gastric adenocarcinoma cases, 14 (70%) showed negative or weak staining of fascin-1, whereas nearly one-third (30%) had moderate or strong expression. Among the 60 poorly differentiated gastric adenocarcinomas, 32 (53.3%) exhibited moderate or strong fascin-1 expression; fewer than half of the cases showed negative or weak staining. Higher intensity of cortactin and fascin-1 staining correlated directly with more-advanced cancer stages (TNM) and inversely with survival rates. Our findings suggest the possibility that pharmacological inhibitors of cortactin and fascin-1 activity may slow down tumor progression and prolong survival time in patients with gastric adenocarcinomas.     

Computer-assisted grading of adenocarcinoma in prostatic aspirates

Conventional cytologic grading of fine needle aspirates of prostatic adenocarcinoma has been shown neither to be reproducible nor to correlate well with histologic grading. This study developed a tumor grade classification based on computerized cytomorphometric features and compared the results to conventional grading of companion tissue sections. The image analysis system evaluated architectural features of the aspirates (mainly cell cluster features and interrelationships) as well as nuclear features. Thirty-five prostatic adenocarcinomas (8 well, 19 moderately and 8 poorly differentiated) were evaluated. Discriminant functions based on data collected at medium and high resolution distinguished between aspirates from low-grade (well-differentiated) and high-grade (poorly differentiated) adenocarcinomas with 81% accuracy. Moderately differentiated cancers could not be classified as a distinct group. This study suggests that accurate grading of prostatic adenocarcinoma in fine needle aspirate smears requires the evaluation of medium-resolution features related to specimen cellularity and uniformity or crowding of cell clusters as well as of high-resolution features of nuclear area, perimeter and coarseness of chromatin texture. These findings are compared to those of other schemes for the cytologic grading of prostatic aspirates.     

C-erbB-2 oncoprotein in gastric carcinoma: correlation with clinical stage and prognosis

The aim of this study was to investigate the expression of the oncogene c-erbB-2 in gastric tumors. Immunohistochemical study of the expression of c-erbB-2 was performed in formalin-fixed, paraffin-embedded sections from 82 gastric adenocarcinomas using polyclonal antibody. c-erbB-2-positive immunostaining was observed in 37 (45%) tumors. Positive staining was detected in 63% of well differentiated, 46% of moderately differentiated and 80% of papillary adenocarcinomas. In poorly differentiated adenocarcinomas, positivity for c-erbB-2 was observed in 21 %. According to the Lauren classification, a higher frequency of c-erbB-2 positive staining was observed in intestinal type tumors (70%). During the follow-up period 43% of the patients with c-erbB-2 oncoprotein-negative tumors and 45% of the patients with c-erbB-2 oncoprotein-positive tumors died. There was no significant association between c-erbB-2 staining and sex, age, clinical stage, tumor grade, histological type or survival rates. In conclusion, almost half of the gastric cancers were positive for c-erbB-2. Nonetheless, the expression of c-erbB-2 oncoprotein did not play a role in prognosis.     

Immunohistochemical studies of colorectal carcinoma with a monoclonal antibody against carcinoembryonic antigen

Immunoperoxidase localization of carcinoembryonic antigen (CEA) was performed on tissue sections of colorectal carcinoma using a monoclonal antibody (MAb) against CEA. CEA has been demonstrated in 20 out of 22 rectum carcinomas (90.9%), in all of 23 colonic carcinomas, in none of 4 hyperplastic polyps and in 2 out of 6 adenomatous polyps (33.3%). CEA was found more often, and the intensity of the staining was stronger in well-differentiated carcinomas than in moderately and poorly differentiated carcinomas. No correlation was found between the presence of CEA in colorectal carcinoma and the stages of the disease. The mean values of serum CEA in patients with colorectal carcinoma and polyps with negative, weakly and strongly positive staining were 5.4 +/- 3.9 ng/ml, 28.3 +/- 23.8 ng/ml and 99.8 +/- 145.3 ng/ml respectively. Elevation of serum CEA occurred in 30 out of 39 (78.9%) cases with strongly positive CEA staining, in 4 out of 6 (66.7%) with weakly positive and in 1 out 9 (11.1%) with negative staining. A significant difference was found in serum CEA activity between the group with negative CEA staining and positive CEA staining (P less than 0.01). Our results suggest that the monoclonal antibody (MAb C27) can be used for the localization of CEA in conventionally prepared tissues of colorectal carcinomas by immunoperoxidase techniques for routine immunopathological diagnosis.     

Expression of IAP family proteins in colon cancers from patients with different age groups

Members of the inhibitor of apoptosis protein (IAP) family including survivin, are expressed in many tumors. However, age-related changes in their expression in cancer have not been clarified. Thus, we investigated the expression of mRNA-coding for IAP family proteins in colon cancer samples from young (<70 years of age) and elderly (>70 years) patients by real-time quantitative RT-PCR. Samples were collected from cases with well-differentiated adenocarcinoma or moderately differentiated adenocarcinoma and their adjacent normal epithelial tissue. Well-differentiated adenocarcinoma tended to express higher levels of survivin than normal mucosa, and expression in moderately differentiated adenocarcinoma was significantly greater than in normal mucosa in samples from both groups of patients (p<0.05, respectively). When samples were compared between the different age groups, the normal mucosa exhibited similar levels of survivin expression. However, samples from older patients showed a significantly higher level of expression than those from younger patients in well and moderately differentiated adenocarcinomas (p<0.05, respectively). In contrast, the levels of expression of cIAP1, cIAP2, and NAIP in the cancerous tissues were lower than those found in normal mucosa regardless of age. As for age-related changes, the expression of cIAP2 in normal mucosa and moderately differentiated adenocarcinoma was stronger in the elderly group than the young group (p<0.05, respectively), and NAIP expression in well-differentiated adenocarcinoma was higher in the young group than the elderly group (p<0.05). XIAP expression was similar in normal and cancerous tissues in both the young and elderly groups. These results suggest that the expression of IAP family proteins, especially survivin, is associated with the age-related biological characteristics of colon cancer.     

Clinical significance of serum gastrin levels in patients with colorectal cancer

AIMS: An association between elevated serum gastrin levels and the presence of human colorectal cancer has been reported, and gastrin has been shown to stimulate the growth of experimentally induced colon neoplasia. The aim of this study was to determine the preoperative and postoperative concentrations of serum gastrin in 53 patients with colorectal cancer and to assess the correlation between gastrin levels and tumor characteristics and prognosis. MATERIALS AND METHODS: A prospective study was performed over a six-year period during which 53 patients received potentially curative surgery for colorectal cancer. The prognostic variables used for the analysis included age, sex, tumor site, stage and degree of differentiation, preoperative and postoperative serum values of carcinoembryonic antigen (CEA) and gastrin, cancer-related mortality, and survival. CEA and gastrin serum values were determined using radioimmunological methods. Follow-up was carried out with clinical and radiological tests. RESULTS: The mean preoperative gastrin concentration was 51.2+/-27.4 pg/mL (range 12-146). Significantly increased serum gastrin concentrations, which returned to normal after surgery, were detected only in patients with well-differentiated cancer (74.2+/-28.3 pg/mL; moderately differentiated, 52.1+/-23.8; poorly differentiated, 29.9+/-12.3, p=0.02). The prognosis was unrelated to serum gastrin level; instead, tumor stage, preoperative CEA value, and degree of differentiation affected patient survival. CONCLUSIONS: This study showed that the serum gastrin concentration is not an appropriate clinical oncogenic factor. Although occurring only in well-differentiated tumors, serum gastrin is unrelated to the prognosis of patients with colorectal cancer.     

Phosphorylated extracellular signal-regulated kinases are significantly increased in malignant mesothelioma.

Tumorigenesis is associated with the activation of mitogenic signal transduction pathways. The expression of activated extracellular signal-regulated kinase (p-ERK) may play an important role in cell proliferation of malignant mesothelioma (MM). We compare the expression of p-ERK in 50 biopsy specimens of MM, non-small-cell lung cancer (NSCLC), and normal lung tissue. We hypothesized that phosphorylated extracellular signal-regulated kinase is increased in MM. We stained the sections by immunohistochemistry for activated ERK-1 and -2 and performed the quantification of the stained nuclei. Quantitative analysis of p-ERK showed a high percentage score in MM (30.3 +/- 4.6%) as compared with NSCLC (12.2 +/- 2.1%) (p<0.01) and control lung tissue (6.4 +/- 1.3%) (p=0.0002). Furthermore, p-ERK was found significantly higher in poorly differentiated NSCLC (17.7 +/- 3.1%) as compared with well-differentiated NSCLC (5.4 +/- 1.2%) (p<0.01). Our data show that the nuclear quantification of p-ERK is significantly increased in MM and poorly differentiated NSCLC in comparison to well-differentiated NSCLC and normal lung tissue. These results corroborate previous experimental studies that suggest a critical role of p-ERK in cell proliferation of malignant disease and may represent new targets for therapeutic agents.     

SM047 immunoreactivity in peritoneal fluids

SM047 is a recently developed monoclonal antibody generated against an ovarian adenocarcinoma cell line. A recent immunohistochemical study has shown that SM047 is strongly expressed in tissue sections of most ovarian serous adenocarcinomas. This study aimed to ascertain whether SM047 staining is of value in cytological preparations of peritoneal fluid. A total of 206 consecutive peritoneal fluids were stained immunocytochemically with SM047, CA125, monoclonal carcinoembryonic antigen (mCEA), Ber-EP4 and cytokeratins (CK7 and 20). SM047 positivity was present in reactive mesothelial cells in 117 of 141 (83%) benign cases in which these were present. SM047 positive tumour cells were present in 22 of 23 (96%) ovarian serous adenocarcinomas and in small numbers of gastric adenocarcinomas (two of three), mesotheliomas (one of two) and pancreatic adenocarcinomas (one of one). All six colorectal and two breast adenocarcinomas were negative with SM047. Reactive mesothelial cells in all cases were positive with CK7 and in most cases with CA125. They were negative with CEA, Ber-EP4 and CK20. All adenocarcinomas were positive with Ber-EP4 and mesothelial cells were always negative. All colorectal adenocarcinomas were positive with CK20. This study shows that SM047 staining may be of value in the diagnosis of an ovarian serous adenocarcinoma in peritoneal fluids. Negative staining helps to exclude a primary ovarian serous adenocarcinoma and is characteristic of colorectal adenocarcinoma. The small numbers of other malignancies in the study precludes a judgement of the value of SM047 staining in these neoplasms. SM047 staining may be useful, as part of a larger panel, in the work up of patients with peritoneal effusions.     

Evaluation of DNA and nuclear protein features for their use in describing normal and malignant endometrium

Different feature sets (geometric, densitometric, and textural) derived from DNA and nuclear protein staining were evaluated for their use in describing atrophic, secretory, and proliferative endometrium, and well-differentiated stage I and moderately differentiated stage I adenocarcinomas of the endometrium. It was found that the pattern of significant differences among these groups varied between feature sets, while remaining consistent within a set of features. The DNA density and run-length features were not very effective in describing group mean differences, whereas the co-occurrence features revealed significant differences among most groups. The protein run-length features were the only ones that consistently showed a difference between proliferative endometrium and well-differentiated adenocarcinomas. Analyses repeated on only cells in the G0/G1 DNA region improved the differentiation between moderately differentiated adenocarcinomas and the other groups. It was concluded that the use of DNA and nuclear protein texture features are effective in describing group differences that cannot be described by DNA content only.     

抑癌基因p53 在肝癌组织中的异常表达及临床意义

目的:探讨抑癌基因p53在肝癌组织中表达及临床意义,为肝癌的治疗提供新的思路。方法:回顾性分析了2006年1月～2009年8月收治的40例肝癌患者的临床资料,采用免疫组织化学法测定肝癌组织、癌旁组织和正常组织中抑癌基因p53的表达,并分析不同肿瘤分化程度患者p53的表达。结果:p53阳性表达率在在肝癌组、癌旁组分别为47.5%和2.5%,在正常组未检测到p53阳性表达,三组之间比较有显著性差异(x2=6.515,P=0.024);高分化癌P53蛋白阳性表达率低,中低分化癌P53蛋白阳性表达率高,组比较均有显著性差异(P<0.05),中、低分化组之间比较差异无统计学意义(P>0.05)。结论:在肝癌组织中存在p53基因的高表达,其阳性表达与肿瘤分化程度有关。     

Significance of progesterone receptor-A and -B expressions in endometrial adenocarcinoma

The progesterone receptor (PR) has two isoforms, A and B, among which PR-B is mainly involved in regulating proliferation of the uterine endometrium. In this study, immunohistochemical analysis was carried out to investigate the correlation of PR-A and -B expressions with cell cycle-regulatory proteins and clinicopathological parameters in endometrial adenocarcinoma. One hundred and forty-one endometrioid adenocarcinomas [76 with well-differentiated (G1), 35 with moderately differentiated (G2) and 30 with poorly differentiated (G3)] were used. Specimens of formalin-fixed and paraffin-embedded tissue were immunohistochemically stained using the high polymer method (HISTOFINE, NICHIREI). The percentage of positive nuclei of tumor cells observed in three high power fields was expressed as a labeling index (LI). PR-B expression significantly occurred more frequently in G1. It was inversely correlated with p53 gene mutation and p53 over expression, and also with clinicopathological variables, including myometrial and lymph-vascular space invasion and the FIGO stage. Patients with negative PR-B had a poorer prognosis than positive cases. PR-A expression was also significantly higher in G1 and was inversely correlated with Ki-67 expression and myometrial invasion, but not with prognosis. PR-A and -B expressions were significantly correlated with biologically malignant potential. Especially, PR-B expression is useful as a prognostic indicator of endometrial adenocarcinoma.     

大肠癌P21,P53蛋白表达和k—ras基因,P53基因突变研究

用免疫组化技术和ＰＣＲ－ＳＳＣＰ技术对高、中、低分化大肠腺癌、癌旁粘膜、正常粘膜及大肠腺癌型息肉的Ｐ２１、Ｐ５３蛋白表达和ｋ－ｒａｓ基因、Ｐ５３基因突变进行检测。结果,大肠腺癌Ｐ２１、Ｐ５３蛋白表达比大肠腺瘤增多,但增加不显著（Ｐ〉０．０５）,二组均比癌旁粘膜和正常粘膜Ｐ２１、Ｐ５３蛋白表达阳性率高（Ｐ〈０．０１）,大肠腺癌ｋ－ｒａｓ基因和Ｐ５３基因突变率比大肠腺瘤、癌旁粘膜和正常粘膜组显著增加     

Neuroendocrine cells within colorectal tumours induced by dimethylhydrazine

Summary Colorectal adenocarcinomas were induced in male Wistar rats, by weekly subcutaneous administration of 1,2-dimethylhydrazine, classified according to the degree of differentiation and submitted to immunocytochemistry for the peptides cholecystokinin (CCK), gastrin, gastric inhibitory polypeptide (GIP), glucagon, neurotensin, pancreatic polypeptide (PP), peptide YY (PYY), somatostatin and vasoactive intestinal polypeptide (VIP) and the biogenic monoamine 5-hydroxytryptamine. Well- or moderately well-differentiated adenocarcinomas comprised 46% of the tumour population, only 4% were poorly-differentiated adenocarcinomas, and the remaining 50% possessed a mixture of these two morphologies. Glucagon, PYY and 5-hydroxytryptamine immunoreactive cells were frequently observed within well- or moderately well-differentiated tumours and within such regions of tumours possessing a mixed morphological pattern. The tumours contained no cells immunoreactive for any of the peptides not normally located within the colorectum, nor did they contain cells immunoreactive for somatostatin and VIP, although known positive controls did stain. Poorly-differentiated tumours and portions of tumours of mixed type, were consistently negative. 5-hydroxytryptamine was the most frequently located of the three antigens, being detected in 87% of the moderately well-differentiated tumours and 32% of the tumours with mixed morphologies. 11% of moderately well-differentiated tumours possessed 5-hydroxytryptamine positive cells in such profusion that they contributed significantly to the tumour mass. The distribution of glucagon-and PYY-immunoreactive cells was similar, although they occurred with a lower frequency, presumably corresponding to their lower numbers within the normal colorectal mucosa. Additionally, these two peptide immunoreactivities were colocalized in the majority of cells, although some cells contained only one antigen. The immense numbers of cells immunoreactive for peptides and monoamine in a significant proportion of colorectal adenocarcinomas suggests that they have arisen from multipotential endodermal stem cells within the tumours and are not part of the normal epithelial population being engulfed as the tumour grows.     

Immunohistochemical demonstration of the carbonic anhydrase isoenzymes I and II in pancreatic tumours

Summary The location of carbonic anhydrase (CA) isoenzymes I, II and VI in normal and neoplastic pancreatic tissue was studied using polyclonal antisera and the immunoperoxidase technique. Samples were obtained from patients with well-differentiated (n = 4), moderately differentiated (n = 1) and poorly differentiated (n = 4) ductal adenocarcinomas, cystadenocarcinoma (n = 2), adenosquamous carcinoma (n = 1), acinar adenocarcinoma (n = 1), gastrinoma (n = 3), insulinoma (n = 3) and glucagonoma (n = 1). The control specimens were from a patient with traumatic laceration of the pancreas. The normal and malignant endocrine tissue showed intense positive staining for CA I localized in the cells expressing glucagon. In the exocrine pancreatic tissue, CA II was detected in the normal and neoplastic ductal epithelium. No specific staining was detected with anti-CA VI serum in either normal or malignant tissue.     

Serrated Pathway Adenocarcinomas: Molecular and Immunohistochemical Insights into Their Recognition

Introduction

Colorectal adenocarcinomas (CRC) developed through serrated pathway seem to present particular behavior compared with the non-serrated ones, but recognition of them is difficult to do. The aim of our paper was to establish some criteria to facilitate their identification.

Materials and Methods

In 170 consecutive CRCs, we performed immunohistochemical staining with Cytokeratin 7 (CK7) and Cytokeratin 20 (CK20) and also with p53 and MLH-1. At the same time, we analyzed BRAF and K-ras mutations and the microsatellite status of CRC.

Results

26.47% of cases expressed CK7, and 16.47% were CK20-negative. Diffuse positivity for CK7 was associated in the proximal colon with CK20 negativity or weak positivity, BRAF mutations, lack of K-ras mutations, and p53 and MLH-1 negativity. All these cases were microsatellite-unstable and were diagnosed in stage II. Those cases from the distal colon and rectum that expressed CK7 were K-ras-mutated and had low p53 index and MLH-1 positivity, independent of the CK20 expression.

Conclusions

CK7, associated with MLH-1 and p53 expression, and also with the microsatellite status, BRAF and K-ras pattern, might be used to identify the CRC potentially going through serrated pathway. The serrated pathway adenocarcinomas of the proximal colon that do not display the morphological features of this pattern are more frequent CK7+/p53−/MLH-1−/BRAF-mutated/K-ras-wt/MSI cases, but those located in the distal colorectal segments seem to be CK7+/CK20+/p53−/MLH-1+/BRAF wt/K-ras-mutated/MSS cases.