Immunohistochemical analysis of the DNA methyltransferase 3b expression is associated with significant improvements in the discrimination of ulcerative colitis-associated neoplastic lesions.

PURPOSE: Making a clinicopathological diagnosis of dysplasia is crucial. We herein assess the significance of the DNA methyltransferase 3b (DNMT3b) expression as a diagnostic marker of ulcerative colitis (UC)-associated neoplasia. METHODS: Thirty-one patients with long-standing and extensive UC were included in this study. The expression of DNMT3b in non-neoplastic rectal epithelium (non-dysplasia in 31 patients) and colorectal neoplasia (dysplasia in 43 patients and invasive cancer in 34 patients) was determined using immunohistochemistry. The presence of immunoreactive DNMT3b was assessed in the areas with the highest density of cells with positively staining nuclei. DNMT3b was expressed as the percentage of positive cells relative to the total number of cells counted under high power magnification. RESULTS: The DNMT3b expression in neoplastic rectal epithelium (0.76, range 0.59-0.84) was increased compared to that observed in non-neoplastic epithelium (0.32, range 0.18-0.67, P < 0.001). A ROC curve analysis confirmed 0.68 to be the best diagnostic cut-off value for the DNMT3b expression in neoplastic epithelium (area under the curve = 0.810). The sensitivity of the diagnostic test was 66.2 %, the specificity was 86.7 %, the positive predictive value was 95.7 % and the negative predictive value was 36.1 %. The positive likelihood ratio was 4.98 and the negative likelihood ratio was 0.20. The accuracy was 69.9 %. CONCLUSIONS: An immunohistochemical analysis of the DNMT3b expression was associated with significant improvements in the discrimination of UC-associated neoplastic lesions.

Differentiation between sessile serrated adenoma/polyp and non-sessile serrated adenoma/polyp in large hyper plastic polyp: A Japanese collaborative study.

A hyperplastic polyp (HP) >10 mm is described as a large hyperplastic polyp (LHP). Previous studies have considered LHP and sessile serrated adenoma/polyp (SSA/P) as synonymous. Although HP and SSA/P have previously been morphologically distinguished, differences between LHP and SSA/P have not yet been reported. The present study aimed to define the differences between SSA/P and non-SSA/P in LHP using immunohistochemistry for Ki67. Colorectal serrated lesions (>10 mm) that were completely resected by endoscope and derived from 11 institutions in Japan [Dokkyo Medical University School of Medicine (Mibu), Takahiro Fujii Clinic (Tokyo), Sano Hospital (Kobe), Oda GI Clinic, Hattori GI Endoscopy and Oncology Clinic (Kumamoto), Ohta Clinic (Nagoya), Hiroshima University (Hiroshima), Iwate Medical University (Morioka), Juntendo and Kyorin Universities (Tokyo) as well as Toyama University (Toyama)] affiliated with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) between January 2003 and December 2010 were selected. The histological criteria of the Japanese Society for Cancer of the Colon and Rectum (JSCCR, project meeting; editor-in chief, Takashi Yao) were used to distinguish SSA/P and non-SSA/P from LHP. Non-SSA/P comprises both incomplete SSA/P and HP. A total of 154 samples diagnosed as SSA/P or non-SSA/P from 148 patients were used. This study comprised 107 SSA/P and 47 non-SSA/P cases, whereby lesions were located on the right side of the colon (73.2 and 26.8%, respectively). Ki67-positivity in SSA/Ps was significantly higher compared to non-SSA/Ps. A greater number of SSA/Ps in LHP were located on the right side of the colon compared to the left side. SSA/Ps occurring on the right side of the colon may be precursor lesions of colorectal carcinoma in serrated neoplasia pathways. In conclusion, LHPs and SSA/Ps limited to the right side of the colon are suggested to be clinically treated as the same type of lesions.

An assessment of the diagnostic criteria for sessile serrated adenoma/polyps: SSA/Ps using image processing software analysis for Ki67 immunohistochemistry.

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 <10 mm. 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.

Clinicopathological features of serrated adenocarcinoma defined by Mäkinen in dukes' B colorectal carcinoma.

OBJECTIVE: Serrated adenocarcinoma (SAC), proposed as a new pathologic type, arises predominantly in the right side of the colon and has a poorer prognosis than conventional colorectal carcinoma. The prognosis of colorectal carcinoma is variable in Dukes' B, so the aim of this study was to determine whether or not SAC has a poor prognosis in Dukes' B. METHODS: The study group comprised 64 patients who underwent surgery for colorectal carcinoma. We undertook a statistical analysis of the association of SAC and non-SAC with sex, age, histologic type, depth of tumor, location of tumor, venous invasion and lymphatic invasion. RESULTS: SACs were encountered in 17.5% of cases (n = 11). SAC had a less favorable 5-year survival than non-SAC (p = 0.0396 log-rank, Kaplan-Meier). The factors that achieved statistical significance in the univariate analysis were subsequently included in a multivariate analysis and we found that SAC was an independent factor (p = 0.027). CONCLUSIONS: SAC has a poor prognosis and is not affected by other factors confirming that SAC is an independently less favorable prognostic factor.

DMBT1 is a novel gene induced by IL-22 in ulcerative colitis.

BACKGROUND: Interleukin (IL)-22 is a recently identified cytokine that is suggested to play pivotal roles in various inflammatory diseases. Although the IL-22 receptor 1 (IL-22R1) is restrictively expressed in epithelial cells in the colon, the role of IL-22 in colonic diseases still remains unclear. In this study microarray analyses revealed that deleted in malignant brain tumors 1 (DMBT1) is a novel upregulated gene in IL-22-stimulated colon cancer cells. Therefore, we investigated the involvement of DMBT1 and IL-22 in ulcerative colitis (UC) tissues and examined the mechanism regulating the expression of DMBT1 in response to IL-22 stimulation. METHODS: Changes of gene expression in IL-22-stimulated SW403 cells were investigated by microarray analyses. The effects of IL-22 on DMBT1 expression were examined in SW403 cells using a small interfering RNA (si)RNA for STAT3 or inhibitors for MEK, PI3K, and nuclear factor kappa B (NF-κB). The element responsible for IL-22-induced DMBT1 promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay (EMSA). Expression of IL-22, IL-22R1, and DMBT1 in UC tissues was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: IL-22 treatment enhanced the expression of DMBT1 through STAT3 tyrosine phosphorylation and NF-κB activation in colon cancer cells. The IL-22-responsive element was located between -187 and -179 in the DMBT1 promoter region. In the UC mucosa the levels of DMBT1 and IL-22 mRNA expression were significantly enhanced and positively correlated, the numbers of IL-22-positive lymphocytes were increased, and the expression of IL-22R1 and DMBT1 was enhanced in the inflamed epithelium. CONCLUSIONS: The IL-22/DMBT1 axis may play a pivotal role in the pathophysiology of UC.

Detection of desmoplastic reaction in biopsy specimens is useful for predicting the depth of invasion of early colorectal cancer: a Japanese collaborative study.

BACKGROUND: We have previously demonstrated a relationship between the depth of submucosal invasion (SM depth) and the frequency of lymph node metastasis in resected submucosal invasive colorectal cancers (SICRCs). Here, we assessed the desmoplastic reaction (DR) in pretreatment biopsy specimens of SICRC to predict the SM depth. METHODS: A total of 359 patients with SICRCs, who had undergone surgical or endoscopic mucosal resection, were enrolled. The SM depth of the SICRC lesions was evaluated according to the procedure established by the Japanese Society for Cancer of the Colon and Rectum, and the patients' corresponding pretreatment biopsy specimens were examined histologically to evaluate the prevalence of DR. RESULTS: For pedunculated SICRCs, the prevalence of DR in pretreatment biopsy specimens was significantly higher in moderately differentiated than in well-differentiated adenocarcinomas, but was not significantly related to SM depth. For nonpedunculated SICRCs, the prevalence of DR in pretreatment biopsy specimens was significantly related to histological type, tumor size, and SM depth. When non-pedunculated SICRCs were further divided using a specific cutoff value of 1000 µm for SM depth, the DR positivity rate in pretreatment biopsy specimens was significantly higher in SICRCs with an SM depth of ≥1000 µm (termed "SM massive CRCs") than in cases where the SM depth was <1000 µm (termed "SM slight CRCs"). CONCLUSIONS: Detection of DR in pretreatment biopsy specimens is useful for the prediction of SM depth in nonpedunculated SICRCs, and may be useful for the selection of such cases that would be treatable by endoscopic mucosal resection and endoscopic submucosal dissection (EMR/ESD).