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Abstract Background Serrated polyps belong to a heterogeneous group of lesions that are generally characterized morphologically. This type of lesion is thought to be the precursor of sporadic carcinomas with microsatellite instability, and probably also the precursor for CpG island-methylated microsatellite-stable carcinomas. For practical purposes, according to the 2010 WHO classification, the diagnostic criteria for sessile serrated adenomas/polyps (SSA/Ps) was established by the research project “Potential of Cancerization of Colorectal Serrated Lesions” led by the Japanese Society for Cancer of the Colon and Rectum. The aim of this study was to evaluate the validity of the morphologic characteristics established in Japan by using immunohistochemical staining for Ki-67. Methods To calculate the target cells, 2 contiguous crypts which could be detected from the bottom of the crypt to the surface of the colorectal epithelium were selected. To validate the proliferative activity, we evaluated the percentage and the asymmetrical staining pattern of Ki67 positive cells in each individual crypt. To examine the immunoreactivity of Ki67, computer-assisted cytometrical analysis was performed. Results SSA/Ps had a higher proliferative activity as compared to hyperplastic polyps (HPs) based on the difference in incidence of Ki67 positive cells, and the former also exhibited a significantly higher asymmetric distribution of these cells as compared to HPs, even in lesions with a diameter Conclusion We conclude that assessment of the pathological findings of SSA/Ps, including crypt dilation, irregularly branching crypts, and horizontally arranged basal crypts (inverted T- and/or L-shaped crypts) is appropriate to show a significantly higher proliferative activity as compared to HPs. Further, the use of two-dimensional image analysis software is an objective and reproducible method for this type of histological examination. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6718091416698112

A total of 313 cases of differentiated-type early gastric adenocarcinomas, including 113 cases of small-sized carcinoma (5< × ≤10 mm) and 121 cases of microcarcinoma (0< × ≤5 mm), were examined immunohistochemically to clarify the phenotypic expressions. They were classified into four categories (gastric phenotype (G-type), intestinal phenotype, gastrointestinal phenotype, and null phenotype) by a two-step process: the phenotype based on an immunoprofile of mucin core proteins (MUCs) with CDX2 (w/.CDX2-assessment); and the phenotype of MUCs only (w/o.CDX2-assessment). CDX2 expression was observed in 89.1% (279/313); it was highly expressed in 87.6% (106/121) of microcarcinomas. MUC2 expression increased as tumor size increased ( P < 0.05). Compared with w/o.CDX2-assessment, w/.CDX2-assessment showed significantly fewer G-type carcinomas ( P < 0.05). Each phenotype marker was less expressed in the submucosal part than in the mucosal part. In conclusion, CDX2 was a sensitive marker for assessing intestinal phenotype. A large portion of the early differentiated-type adenocarcinomas expressed CDX2 from the very early stage of carcinogenesis, and the proportion of G-type was unexpectedly low. Lower expression of each phenotype marker was considered the cause of phenotype alteration during submucosal invasion. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) have a significant risk of metastasis, although the degree varies in each case. The present report describes a case of late recurrence of GIST that was diagnosed 30 years after the primary tumor resection. An 80-year-old man was transported to Sanjo General Hospital (Sanjo, Japan) with hemorrhagic shock from gastrointestinal bleeding. Abdominal contrast-enhanced computed tomography revealed an 11.7-cm heterogenous tumor in the retroperitoneum adjacent to the third portion of the duodenum. The patient had a medical history of resection of 'leiomyoma' of the upper jejunum when he was 50 years old. Pathological examination using archival pathological samples revealed that the previously excised tumor was GIST because the tumor cells showed positive immunoreactivity for KIT and DOG1. Treatment was started with imatinib, a selective KIT tyrosine inhibitor, even though endoscopy failed to provide biopsy specimens. Positron emission tomography conducted on the 28th treatment day revealed that imatinib completely shut down 18F-fluorodeoxyglucose uptake in the tumor, confirming that the tumor was imatinib-sensitive. A literature review yielded 12 GIST cases wherein metastases were diagnosed >10 years after primary tumor resection. Of the 12, four were originally diagnosed as benign. Clinicians should keep in mind that GISTs were formerly confused with non-GIST tumors and that there is a risk of relapse 10 years or later after curative surgery. [ABSTRACT FROM AUTHOR]

Aims Although intestinal-type epithelium in Barrett's oesophagus has been traditionally recognized as having a distinct malignant potential, whether this also holds true for cardiac-type epithelium remains controversial. The aim of this study was to identify a type of epithelium that is highly associated with Barrett's tumour. Methods and results We analysed tumours and the corresponding background mucosa with special regard to tumour size in 40 cases of superficial Barrett's tumour by using immunohistochemical staining for CDX2, CD10, MUC2, MUC5 AC, and MUC6. Intestinal metaplasia in tumour-adjacent mucosa was not associated with tumour size, but was significantly correlated with the extent of Barrett's oesophagus ( P < 0.001). The majority (69.2%, 9/13) of small tumours (≤10 mm) had no intestinal metaplasia in adjacent non-neoplastic mucosae. Minute (≤5 mm) tumours were significantly associated with a gastric immunophenotype ( P < 0.001). Purely gastric-immunophenotype tumour cells expressed CDX2, and cardiac-type epithelium adjacent to small tumours also showed low-level CDX2 expression. Conclusions Our data suggest that intestinal metaplasia in Barrett's oesophagus is an epiphenomenon rather than a preneoplastic condition, and that CDX2-positive cardiac-type epithelium is highly associated with minute Barrett's tumour. Further prospective studies are needed to evaluate the risk of malignancy of cardiac-type epithelium with regard to sub-morphological intestinalization. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated increased levels of DNA double-strand breaks (DSBs) and activation of the DNA damage response (DDR) in precancerous lesions during cancer development. Those observations have not been fully elucidated using paraffin-embedded tissues of colorectal tumors. The aims of this study were to analyze the presence of DSBs and DDR activation mediated by p53- binding protein 1 (53BP1), which is a conserved checkpoint and DNA repair protein, and to clarify their association with colorectal tumor progression. We used immunohistochemical staining to investigate the expression of ?H2AX, a sensitive marker for DSBs, in 152 colorectal tumors (46 low-grade adenomas, 25 high-grade adenomas, 25 intramucosal carcinomas, and 56 invasive carcinomas). The colocalization of ?H2AX and 53BP1, which is strongly associated with the DSB repair process, was analyzed using double-label immunofluorescence. Elevated ?H2AX expression was identified in 16 (16.7%) of 96 intramucosal neoplasias and in 19 (33.9%) of 56 invasive carcinomas. Double-label immunofluorescence occasionally revealed cells, particularly in invasive carcinoma, with ?H2AX foci that did not colocalize with 53BP1. The percentage of tumor cells with ?H2AX foci that colocalized with 53BP1 was significantly lower in invasive carcinoma than in intramucosal neoplasia (median percentage, 54.8% and 88.5%, respectively; P = .001). In conclusion, the number of cells with DSBs increases in intramucosal neoplasia and invasive carcinoma. The decreasing number of cells with colocalization of ?H2AX and 53BP1 during the progression from intramucosal neoplasia to invasive carcinoma suggests that DDR, at least mediated by 53BP1, is inefficient during the process of cancer invasion. [ABSTRACT FROM AUTHOR]

Background and Aim: Histological criteria for intracapsular venous invasion (IVI) that would allow its discrimination between portal and hepatic venous invasion in hepatocellular carcinoma (HCC) have not been established. Methods: We evaluated IVI immunohistochemically to discriminate between portal and hepatic venous invasion in 89 resected specimens from patients with HCC. IVI was defined as the microscopic involvement of the vessels within the fibrous capsule of HCC. The hepatic venous system was subdivided into the central vein and the sublobular/hepatic vein. Immunohistochemical analysis with the D2-40 monoclonal antibody revealed lymphatic vessels. Results: In non-neoplastic liver tissues, the portal veins ( n = 4355) were accompanied by lymphatic vessels (99.7%), bile ductules (100%) and arteries (96%), whereas the central veins ( n = 3932) and sublobular/hepatic veins ( n = 662) were rarely accompanied by lymphatic vessels (0% and 17%, respectively) and bile ductules (12% and 33%, respectively). In total, 29 IVI foci were detected; three foci were clearly visible within vessels that contained a distinct layer of connective tissue fibers, signifying sublobular/hepatic venous invasion. As the remaining 26 foci were accompanied by lymphatic vessels (26/26 [100%]), bile ductules (21/26 [81%]) and arteries (10/26 [38%]), these foci were considered to reflect intracapsular portal venous invasion rather than venous invasion of the central vein. Intracapsular portal venous invasion was significantly associated with extratumoral portal venous invasion ( P < 0.001). Conclusions: D2-40 immunoreactivity for the histological evaluation of IVI in HCC allows discrimination between portal and hepatic venous invasion for cases in which portal venous invasion predominates. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family of immunoglobulin-like adhesion molecules. The aim of this study was to test the hypothesis that loss of CEACAM1 expression in hepatoblastoma cells may promote hematogeneous metastasis and function as an adverse prognostic factor. Methods: Immunohistochemical expression of CEACAM1 in surgically resected specimens from 19 patients with hepatoblastoma was examined retrospectively. The CEACAM1 expression in the epithelial area of the tumor was classified into 2 categories as follows: diffuse expression, characterized by positive staining throughout the tumor specimen, or loss of expression, in which there were distinct areas of negative staining within the tumor specimen. Results: Of the 19 patients, 12 were classified as having tumors with diffuse expression, and 7 had loss-of-expression tumors. Survival after treatment was significantly worse in patients with tumors with loss of CEACAM1 expression (cumulative 5-year survival rate, 29%) than in patients with diffuse CEACAM1 expression (cumulative 5-year survival rate, 92%; P = .0062). Loss of CEACAM1 expression was a significant risk factor for metachronous pulmonary metastases (P = .0105). Conclusions: Loss of CEACAM1 expression may reflect a high metastatic potential and thus indicate a poor prognosis for patients with hepatoblastoma. [Copyright &y& Elsevier]

Summary: This study retrospectively evaluated the immunohistochemical expression of 3 cell adhesion molecules (CAMs), E-cadherin, β-catenin, and osteopontin, according to tumor grade in 125 surgically resected specimens of hepatocellular carcinoma (HCC). The aims of this study were to identify factors associated with vascular invasion and to elucidate the prognostic value of CAMs. The median follow-up time was 110 months. The levels of E-cadherin, β-catenin, and osteopontin immunoreactivity were significantly associated with Edmondson-Steiner grade but not with tumor size. There was increased loss of E-cadherin, nonnuclear overexpression of β-catenin, and overexpression of osteopontin in tumors of higher histologic grade. Vascular invasion was found in 44 (35%) of 125 resected specimens. Logistic regression analysis identified 3 tumor-related factors that were independently associated with vascular invasion—tumor size more than 3 cm, Edmondson-Steiner grades III to IV, and overexpression of osteopontin. Among the tested CAMs, osteopontin (P = .0110) and E-cadherin (P = .0287) were significant prognostic factors by univariate analysis. The Cox proportional hazard regression analysis revealed that Edmondson-Steiner grades III to IV (relative risk [RR], 3.028; P < .001), the presence of vascular invasion (RR, 1.964; P = .011), overexpression of osteopontin (RR, 1.755; P = .034), serum α-fetoprotein level more than 20 ng/mL (RR, 1.834; P = .037), and Child-Pugh classification B to C (RR, 1.880; P = .040) were found to be independently significant factors associated with survival after hepatectomy. These results suggest that overexpression of osteopontin independently correlates with vascular invasion and thus predicts poor survival for patients with HCC, whereas aberrant expression of E-cadherin or β-catenin does not. [Copyright &y& Elsevier]

We have succeeded in raising highly specific anti-human intestinal fatty acid-binding protein (I-FABP) monoclonal antibodies by immunizing animals with three synthetic regional peptides, i.e., the amino terminal (RP-1: N-acetylated 1-19-cysteine), middle portion (RP-2: cysteinyl-91-107) and carboxylic terminal (RP-3: cysteinyl-121-131) regions of human I-FABP, and the whole I-FABP molecule as antigens. We also raised a polyclonal antibody by immunizing with a recombinant (r) I-FABP. To ascertain the specificity of these antibodies for human I-FABP, the immunological reactivity of each was examined by a binding assay using rI-FABP, partially purified native I-FABP and related proteins such as liver-type (L)-FABP, heart-type (H)-FABP, as well as the regional peptides as reactants, and by Western blot analysis. In addition, the expression and distribution of I-FABP in the human gastrointestinal tract were investigated by an immunohistochemical technique using a carboxylic terminal region-specific monoclonal antibody, 8F9, and a polyclonal antibody, DN-R2. Our results indicated that both the monoclonal and polyclonal antibodies established in this study were highly specific for I-FABP, but not for L-FABP and H-FABP. Especially, the monoclonal antibodies raised against the regional peptides, showed regional specificity for the I-FABP molecule. Immunoreactivity of I-FABP was demonstrated in the mucosal epithelium of the jejunum and ileum by immunohistochemical staining, and the immunoreactivity was based on the presence of the whole I-FABP molecule but not the presence of any precursors or degradation products containing a carboxylic terminal fragment. It is concluded that some of these monoclonal and polyclonal antibodies, such as 8F9, 4205, and DN-R2, will be suitable for use in research on the immunochemistry and clinical chemistry of I-FABP because those antibodies can recognize both types of native and denatured I-FABP. In order to detect I-FABP in blood samples, it is essential to use this type of antibody, reactive to native type of I-FABP. It is anticipated that, in the near future, such a method for measuring I-FABP will be developed as a useful tool for diagnosing intestinal ischemia by using some of these antibodies. [ABSTRACT FROM AUTHOR]

In this study we aimed to identify clinically relevant patterns of cytomegalovirus (CMV) infection in inflammatory bowel disease. Twenty-two patients with severe ulcerative colitis (UC), 12 with moderate UC, and 16 with Crohn's disease were studied retrospectively. We confirmed CMV infection immunohistochemically. The patients were classified into three groups according to the density of CMV-infected cells. Clinicopathologic features were compared between the groups. Dense CMV infection was found only in five patients with severe UC. Scattered CMV infection was found in nine patients with severe UC, three with moderate UC, and one patient with Crohn's disease, and in three controls (normal mucosa from early colorectal cancer specimens). For patients with severe UC, severity of CMV infection tended to correlate with older age and more rapid deterioration, including toxic megacolon and panperitonitis. The dense CMV group took significantly higher final daily doses of steroids before the operation, and showed steroid resistance. The frequency of emergency surgery was higher and postoperative hospital stay was significantly longer in the dense CMV group. No significant differences were observed in sex, disease duration, steroid administration (total amount or duration), or frequencies of other therapies among the three groups. Immunohistochemically, CMV positivity in endothelial cells around the ulcer base was a significant feature in dense CMV infection, compared with scattered CMV infection. Older patients with severe steroid-resistant UC may be at particular risk for CMV infection. Dense CMV infection, especially when it occurs predominantly in endothelial cells, may be a useful marker for clinically relevant CMV infection. [ABSTRACT FROM AUTHOR]

Several studies have indicated that administration of non-steroidal anti-inflammatory drugs (NSAID) to patients with familial adenomatous polyposis (FAP) results in a regression of colorectal adenomas through inhibition of cyclooxygenase-2 (COX-2). It is thought that sporadic colorectal adenomas might also be useful targets for the chemoprevention of colorectal cancer, but a marked effect of NSAID on the regression of sporadic adenomas has not been observed. We investigated the immunohistochemical expression of COX-2 in sporadic tubular adenomas (n = 100) from 63 patients and in tubular adenomas (n = 121) from 12 patients with FAP, in order to determine if chemoprevention might be more successful in sporadic adenomas once they have reached a certain size. COX-2 scores were significantly lower (P < 0.0001) in small (< 5 mm in diameter) adenomas than in large (≥ 5 mm) adenomas. This was observed in both sporadic cases and in cases involving patients with FAP. With regard to small (< 5 mm) adenomas, significantly higher (P = 0.02) COX-2 scores were obtained in adenomas resulting from FAP than sporadic adenomas. The variation in COX-2 expression observed among sporadic adenomas of different sizes should be taken into account when making decisions regarding attempts at chemoprevention using NSAID. Sporadic adenomas 5 mm or larger with upregulated COX-2 expression are potentially useful targets for the antiproliferative effects of NSAID. [ABSTRACT FROM AUTHOR]

To study the appropriate period for formalin fixation in order to detect p53 abnormalities in formalin-fixed tissue, we used seven surgically resected human colorectal cancer specimens. The immunohistochemical reactivity of p53 immunostaining and amplification of DNA by polymerase chain reaction (PCR) of the p53 gene were compared after various periods of 10% formalin fixation (1 day, and 1, 2, 4, and 8 weeks). For comparative immunostaining, we used the monoclonal antibody Ki-67 (MIB-1), and for comparative polymerase chain reaction (PCR), K-ras at codon 12 was amplified. Immunostaining was performed by the streptavidin-biotin method with microwave retrieval, and PCR amplifications were performed by the nested PCR method. p53 and Ki-67 immunoreactivity did not change essentially for up to 2 weeks and 1 week, respectively, of formalin fixation. PCR amplification for p53 at exon 8 and K-ras at codon 12 was successful until 1 day and 2 weeks, respectively, of formalin-fixation for the specimens of all seven cases. Thereafter, the amplification tended to worsen as the fixation time lengthened. Further, the DNA was more successfully amplified in the second PCR than in the first. These results suggest that to detect p53 abnormality in specimens that have been formalin-fixed for long periods, immunohistochemical staining may have advantages over DNA analysis with PCR amplification. [ABSTRACT FROM AUTHOR]

Chromophobe renal cell carcinoma (chRCC) patients have good prognosis. Only 5%–10% patients die of metastatic disease after tumorectomy, but tumor progression cannot be predicted by histopathological parameters alone. chRCC are characterized by losses of many chromosomes, whereas gene mutations are rare. In this study, we aim at identifying genes indicating chRCC progression. A bioinformatic approach was used to correlate chromosomal loss and mRNA expression from 15287 genes from The Cancer Genome Atlas (TCGA) database. All genes in TCGA chromophobe renal cancer dataset (KICH) for which a significant correlation between chromosomal loss and mRNA expression was shown, were identified and their associations with outcome was assessed. Genome-wide DNA copy-number alterations were analyzed by Affymetrix OncoScan® CNV FFPE Microarrays in a second cohort of Swiss chRCC. In both cohorts, tumors with loss of chromosomes 2, 6, 10, 13, 17 and 21 had signs of tumor progression. There were 4654 genes located on these chromosomes, and 13 of these genes had reduced mRNA levels, which was associated with poor outcome in chRCC. Decreased CDKN1A expression at mRNA (p = 0.02) and protein levels (p = 0.02) were associated with short overall survival and were independent predictors of prognosis (p < 0.01 and <0.05 respectively). CDKN1A expression status is a prognostic biomarker independent of tumor stage. CDKN1A immunohistochemistry may be used to identify chRCC patients at greater risk of disease progression. [ABSTRACT FROM AUTHOR]

Discrimination between benign and malignant biliary strictures is difficult, with 5.2 to 24.5 per cent of biliary strictures proving to be benign after histological examination of the resected specimen. This study aimed to evaluate the clinicopathological features of benign biliary strictures in patients undergoing resection for presumed biliary malignancy. From January 1990 to August 2010, 5 of 153 (3.3%) patients who had undergone resection after a preoperative diagnosis of biliary malignancy had a final histological diagnosis of benign biliary stricture. The infiltration of immunoglobulin G4-positive plasma cells was evaluated by immunohistochemistry. None of the five patients had a history of trauma or earlier hepatobiliary surgery and all five underwent hemihepatectomy (combined with extrahepatic bile duct resection in three patients). Postoperative morbidity was recorded in two patients (transient cholangitis and biliary fistula), but there was no postoperative mortality. Histological re-examination identified immunoglobulin G4-related sclerosing cholangitis (n = 2) and nonspecific fibrosis/inflammation (n = 3). No preoperative clinical or radiographic features were identified that could reliably distinguish patients with benign biliary strictures from those with biliary malignancies. Although benign biliary strictures are rare, differentiating benign strictures from malignancy remains problematic. Thus, the treatment approach for biliary strictures should remain surgical resection for presumed biliary malignancy. [ABSTRACT FROM AUTHOR]

Abstract: This study used mucin immunohistochemistry to investigate differences in the properties of intestinal metaplasia between the antrum and body of the stomach in 28 resected specimens. Intestinal metaplasia was classified as: (1) small intestinal metaplasia (SIM) with a tubule, including CD10-positive brush border on a background of MUC5AC-/HGM-negative cells; or (2) goblet cell metaplasia (GCM) with MUC2-positive and CD10-negative cells. In the antrum, frequencies of SIM and GCM were nearly equal irrespective of metaplasia grade. Frequency and length of remnant pyloric gland for SIM were significantly greater in the antrum than in the body. In the proliferative zone, there existed a lower level in SIM than in non-intestinalized tubules. These findings suggest that the proliferative zone shifts from the neck zone toward the bottom of the tubule during the SIM process in the antrum. In the body, however, the grade of SIM grade was significantly higher than that of GCM. The proliferative zone was located higher in the fundic gland, pseudopyloric gland and SIM, in that order. Almost all remnant pyloric glands for SIM were negative for pepsinogen I. These facts indicate that SIM in the body originates in a proliferative zone that shifted downward to an area near the bottom of the tubule, with atrophic pyloric glands originating from pseudopyloric gland metaplasia. [Copyright &y& Elsevier]

Liver–intestine cadherin (LI-cadherin) is a recently identified member of the cadherin superfamily. We examined LI-cadherin expression in four human colorectal carcinoma cell lines and 45 human primary colorectal carcinomas using a monoclonal antibody against LI-cadherin. We also investigated the correlation between LI-cadherin expression and clinicopathologic parameters. Among the cell lines, LI-cadherin expression was detected in a differentiated phenotype, but not in dedifferentiated phenotypes. Among the 45 tumor samples, LI-cadherin expression was preserved in 28 (62%) and reduced in 17 (38%). Reduced LI-cadherin expression was significantly associated with a high tumor grade (P=0.015), lymphatic invasion (P=0.033), lymph node metastasis (P=0.015), and an advanced pTNM stage (P=0.033). These results suggest that analysis of LI-cadherin expression may help to indicate the biological aggressiveness of this malignancy. [Copyright &y& Elsevier]