Expression of HER2 and MUC1 in Advanced Colorectal Cancer: Frequency and Clinicopathological Characteristics

There have been many reports on the overexpression of human epidermal growth factor receptor 2 (HER2) in patients with colon cancer. However, the role and frequency of HER2 overexpression have not been clearly defined. Anti-HER2 therapy has been shown to improve the prognosis of HER2-positive patients with breast and stomach cancers. In this study, we explored HER2 expression in patients with colon cancer at stages II and III by immunohistochemistry (IHC) and dual-color in situ hybridization (DISH), and examined the correlation between HER2 expression and clinicopathological factors. Moreover, we examined the correlation between HER2 expression and mucin 1 (MUC1) expression. The subjects were 121 patients with colon cancer at stages II and III who underwent surgery in our hospital during the period from 2007 to 2009. Sections containing the deepest part of a lesion were subjected to immunostaining for HER2 and MUC1. HER2 expression was assessed in accordance with Ventana\u27s Guidelines for HER2 Testing in Stomach Cancer, with sections comprising less than 10% of weakly to moderately stained tumor cells scored as 1 > 2. HER2 expression scored as 2 was defined with sections comprising more than 10% of the weakly to moderately stained tumor cells. Patients with a score of 1 > 2 and 2 were also subjected to DISH using a Dual ISH HER2 kit. MUC1 expression was scored according to the percentage of stained area as follows: 0, 0 to 5%; 1, 5 to 50%; and 2, 50% and higher. Patients with a score of 1 and 2 were defined as MUC1-positive. The analysis of HER2 by IHC yielded the following scores: 45 patients (37.2%), 0; 38 patients (31.4%), 1; 14 patients (11.6%); 1 > 2; 24 patients (19.8%), 2; and 0 patients (0%), 3. For the 38 patients with a score of 1 > 2 and 2, DISH returned ratios of HER2 to Chr17 expression (HER2: Chr17 ratio) from 1.13 to 1.93 (mean = 1.46). There was no significant correlation between HER2 expression and clinicopathological factors. The numbers of MUC1-positive patients according to HER2 score were as follows: 22 patients (48.9%) in the score 0 group (45 patients); 25 patients (65.8%) in the score 1 group (38 patients); 10 patients (71.4%) in the score 1 > 2 group (14 patients), and 22 patients (91.7%) in the score 2 group (24 patients). There was a positive correlation between HER2 expression and MUC1 expression. Specifically, MUC1 expression levels increased with HER2 expression level, and the percentage of MUC1-positive patients was significantly higher in the HER2 score 2 group than in the HER2 score 0 group (P < 0.01). Rates of HER2 positivity by DISH or fluorescence in situ hybridization (FISH) in patients who had an HER2 score of 2+ by IHC were 45% and 24% in the patients with stomach and breast cancers, respectively. However, the positivity rate was 0% in the patients with colon cancer in this study. This result indicates that patients with colon cancer who have an IHC HER2 score of 2+ are more likely to be HER2 negative by DISH than patients with breast and stomach cancers, although larger cohort studies are required before a definitive conclusion can be made. There was a positive correlation between HER2 expression and MUC1 expression in this study, although further examination is required because there were no patients who had an HER2 score of 3+ or 2+ by IHC and were HER2 positive by DISH in this study. HER2 expression in colon cancer should be cautiously assessed by both IHC and DISH

Clinicopathologtcal Study of Serrated Polyps of the Colorectum, with Special Reference to Maspin Expression

Aims: We compared the clinicopathologic features of three types of colorectal serrated polyps, namely, hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs), and analyzed the expression pattern of maspin in these serrated lesions. We retrospectively examined 173 polypoid lesions that were endoscopically excised from 136 patients and diagnosed as hyperplastic or adenomatous serrated lesions, and histologically classified as HPs, SSA/Ps, or TSAs. Maspin expression was immunohistochemically examined in all lesions. Overall, 59 lesions (34%) were classified as HPs, 70 (40%) as SSA/Ps and 44 (25%) as TSAs. There were no significant differences in mean age or gender of patients between types, but SSA/Ps frequently developed on the right colon and showed a superficial/flat elevation, whereas HPs and TSAs frequently developed on the left colon and showed protruded lesions. The average diameters of HPs, SSA/Ps, and TSAs were 7.2, 9.9, and 12.9mm, respectively, showing significant differences. Diffuse cytoplasmic expression of maspin was observed in the serrated glands of all three types. In addition, focal or diffuse intranuclear localization of maspin was observed in 15% of HPs, 13% of SSA/Ps, and 84% of TSAs, showing significant differences between TSAs and the other two types. The three types of serrated polyp examined in this study showed distinct clinicopathological features. The presence of maspin expression in these polyps, regardless of whether they were hyperplastic or neoplastic, indicates that maspin might be commonly associated with cell proliferation, although the underlying mechanism might be different between types

A Clinicopathological Study of Primary Small Intestinal Cancer with Emphasis on Cellular Characteristics

We examined the clinicopathological profiles and cellular characteristics of 10 cases of surgically resected primary small intestinal cancers (excluding duodenal cancers). Histological examination revealed nine adenocarcinomas and one sarcomatoid carcinoma. Invasion depth was subserosal in five cases, serosal in four cases and to the adjacent transverse colon in the remaining case. Metastasis was present in lymph node in seven cases, in distant organs in six, and in the peritoneum in seven cases. Of the 10 cases, 7 underwent postoperative chemotherapy, and 6 of the eight traceable patients died from the disease (mean period of survival: 386 days). Histomorphologically, eight of nine adenocarcinomas showed an intestinal phenotype (unclassifiable in the other) in the upper layer, while in the lower layer, there showed an intestinal phenotype and five a non-intestinal phenotyp. Immunohistochemistry revealed a mean positive rate in the upper/lower layers as follows: 93%/86% and 38%/29% by intestinal markers CDX2 and MUC2; 19%/28% and 13%/32% by pancreatobiliary markers CK7 and MUC1; and 4%/19% and 2%/9% by gastric markers MUC5AC and MUC6, respectively. Thus, the intestinal phenotype predominated in almost all small intestinal cancer in this study, although some showed a transformation to non-intestinal or hybrid phenotypes with tumor progression. Flexible management for the diversity and transformation of cellular characteristics is therefore recommended treating and diagnosing small intestinal cancers

Clinicopathological Significance of FOXP3 Expression in Esophageal Squamous Cell Carcinoma

The expression of transcription factor forkhead box protein 3 (FOXP3), a master control gene for regulatory T cells, has been reported to influence patient survival. However, there have been few reports of the relationship between FOXP3 positive cells and esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the prognostic value of FOXP3 expression in ESCC. Ninety-five patients who were diagnosed with primary ESCC and underwent subtotal esophagectomy during 2009 and 2010 were retrospectively analyzed. Deepest sections from each tumor were selected for immunohistochemistry and the number of FOXP3 positive cells was counted. The median number was used as a cutoff to divide into FOXP3 positive and FOXP3 negative subgroups. Relationships between FOXP3 expression and clinicopathological features, disease-free survival (DFS) and overall survival (OS) were determined. Statistical values of p < 0.05 were considered significant. FOXP3 positive cells were found in all 95 cases and the number of FOXP3 positive cells was significantly higher in the peri-tumor compartment than in the intra-tumor compartment (p = 0.0006). For this reason, the peri-tumor compartment numbers were used for all of the association studies. Results showed that the FOXP3 positive group had a significantly larger mean tumor size (43.8 ± 4.1mm vs 29.1 ± 4.0mm, p = 0.0055), and the FOXP3 negative group had a significantly higher percentage of deep invasion (T2, T3, T4)(p = 0.0399). There was no significant association for DFS, however, for OS the FOXP3 positive group demonstrated a significantly better prognosis (p = 0.0024). Multivariate analysis showed that peri-tumor FOXP3 expression is an independent prognostic factor for OS (p = 0.0035). Peri-tumoral FOXP3 expression is an independent and favorable prognostic factor for ESCC

Poly ADP-ribose Polymerase (PARP) Staining for Immunohistological Investigation of Primary Breast Cancer

Given that clinical trials of poly ADP-ribose polymerase (PARP) 1 inhibitors are underway, in the present study we investigated the prevalence of triple-negative breast cancer and PARP1 expression in patients with primary invasive breast cancer. Immunohistological studies plus PARP staining were performed on samples from 206 primary breast cancer patients undergoing surgery at Showa University Hospital between January 2010 and May 2011. Fifteen patients (7.3%) were found to have triple-negative breast cancer. Hormone receptor-positive patients were significantly more likely to be PARP1 negative. There were no PARP1-negative patients in the triple-negative group. However, there was no significant difference in the rate of PARP1 negativity between patients with triple-negative breast cancer and those with other breast cancer subtypes. There were no PARP1-negative patients in the triple-negative breast cancer group. Given that the effectiveness of PARP inhibitors has not been sufficiently established in clinical trials, a more in-depth analysis is required to determine the factors contributing to effective treatment. Future studies should include more subjects with triple-negative breast cancer and those with BRCA mutations

A Case of Unusual Polypoid Mixed Hemangioma of the Sigmoid Colon: Possibly an Angioadenomatous Polyp

Herein, we report on an unusual case of polypoid mixed hemangioma of the sigmoid colon. An 85-year-old woman who underwent colonoscopic examination was found to have a smooth, red polypoid tumor, 6mm in diameter, in the sigmoid colon. The polyp was resected endoscopically. Microscopically, the polyp contained two pathologic components: (i) adenomatous proliferative glands as the epithelial component; and (ii) mixed hemangioma as the mesenchymal component. On the basis of these findings, a pathological diagnosis of angioadenomatous polyp was made. Although seven previous cases of polypoid hemangioma located in the submucosa have been reported in the literature, the present case is the first in which the hemangioma is localized only in the mucosa. The mixed hemangioma may be the pathogen stimulating the adenomatous proliferation of the glands