Yasuyo Ohi

Expression of maspin predicts poor prognosis in breast-cancer patients

The tumor suppressor gene maspin has been reported to inhibit the invasiveness and motility of breast cancer cells. It has been reported that maspin is expressed in normal human mammary epithelial cells but is downregulated during cancer progression, and that p53 could induce maspin expression by transcriptional activation. However, to date, the clinical significance of maspin expression and its correlation with p53 protein expression in human breast cancer patients have not been elucidated. One hundred and sixty‐eight female patients diagnosed with invasive ductal carcinoma, who had undergone a mastectomy (154 patients) or breast‐conserving surgery (14 patients), were followed up for 15–119 months (median: 87 months) postoperatively. Immunoreactivity for maspin and p53 antibodies with paraffin‐embedded carcinoma tissue was investigated using labeled streptavidin‐biotin methods. Tumors with more than 20% of positive cells were considered positive for the expression of maspin. The expression of maspin in carcinoma cells was found in 27.4% (46 of 168) and significantly correlated with larger tumor size (p = 0.008), higher histologic grade (p = 0.0001) and positive p53 status (p = 0.003). A significant inverse relationship was observed between the expression of maspin and estrogen receptor (p = 0.0004) or progesterone receptor status (p = 0.02). Univariate analysis by log‐rank test revealed a significant association between the expression of maspin and shorter relapse‐free survival (p < 0.0001) and overall survival (p < 0.0001). According to Coxs multivariate analysis, the expression of maspin had the most significant effect in relapse‐free survival (p < 0.0001) and overall survival (p < 0.0001) followed by lymph node status. In turn, the expression of maspin in 58 cases of ductal carcinoma in situ were also investigated to explore whether the downregulation of maspin through cancer progression are true or not. However, there were no positive cases in our series. These results seem to be contrary to previous reports defining maspin as a tumor suppressor gene. Although more precise characterization of the maspin expression, especially gene analysis is essential, the present investigation suggests that the expression of maspin is not downregulated through malignant progression and that the immunohistochemic detection of maspin in carcinoma cells may be helpful for selecting the group of breast cancer patients with an aggressive phenotype.

An international study to increase concordance in Ki67 scoring

Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 ‘training’ and ‘test’ web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90–0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.

Co-expression of epidermal growth factor receptor and transforming growth factor-α predicts worse prognosis in breast-cancer patients

Epidermal growth factor receptor (EGF‐R) and its ligand, transforming growth factor‐α (TGF‐α), play an important role through the autocrine growth‐regulation system in several human cancers, including breast cancer. However, the clinical significance of co‐expression of EGF‐R and TGF‐α has not been elucidated. One hundred seventy‐three female patients diagnosed as invasive ductal carcinoma who had undergone a mastectomy (159 patients) or breast‐conserving surgery (14 patients) were followed up for 81 to 119 months (median 94 months) post‐operatively. Immunoreactivity for EGF‐R, TGF‐α, p53 and c‐erbB‐2 with paraffin‐embedded carcinoma tissue was investigated using labeled streptavidin‐biotin methods. Positive rates of carcinoma cells were 27%, 33%, 32% and 26% for EGF‐R, TGF‐α, p53 and c‐erbB‐2, respectively. Expression of EGF‐R only was observed in 16% (28/173), of TGF‐α only in 22% (38/173), of both EGF‐R and TGF‐α in 11% (19/173) and of neither in 51% (88/173). By univariate analysis, significant differences in overall survival and disease‐free survival were noted according to the co‐expression of EGF‐R and TGF‐α (p < 0.0001, p < 0.0001), co‐expression of EGF‐R and c‐erbB‐2 (p = 0.0029, p = 0.0028), nodal status (p = 0.0028, p = 0.0001), tumor size (p = 0.0001, p < 0.0001) and c‐erbB‐2 expression (p = 0.0034, p = 0.018), respectively. The status of p53 expression (p = 0.01), estrogen receptor (p = 0.042) and progesterone receptor (p = 0.046) showed significant differences in overall survival. According to Coxs multivariate analysis, co‐expression of EGF‐R and TGF‐α had the most significant effect on disease‐free survival (p < 0.0001) and overall survival (p < 0.0001), followed by nodal status. Co‐expression of EGF‐R and TGF‐α by immunohistochemical detection is an independent prognostic indicator, and it may be helpful for determining the group of breast‐cancer patients with an aggressive phenotype. Int. J. Cancer 89:484–487, 2000.

Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor‐negative breast cancer patients

CyclinD1 plays a critical role in regulating cell cycle progression. CyclinD1 mRNA and protein are overexpressed in approximately 50% of primary breast cancer cases. However, its clinical significance as a predictive factor remains unclear. One hundred and seventy‐three female patients diagnosed with invasive ductal carcinoma who had undergone a mastectomy (161 patients) or breast‐conserving surgery (12 patients) were followed up for 6–119 months (median 86 months) postoperatively. Immunoreactivity for monoclonal anti‐cyclinD1 antibody (clone DCS‐6) with paraffin‐embedded carcinoma tissues was investigated using a labeled streptavidin‐biotin method. Overexpression of cyclinD1 was found in 42% (73 of 173), and strongly correlated with estrogen receptor (ER) expression (p < 0.000001). Univariate analysis revealed no association between overexpression of cyclinD1 and overall survival or relapse‐free survival in all patient groups. However, in the ER‐negative subgroup (n = 75), overexpression of cyclinD1 was significantly correlated with shorter overall survival (p = 0.018) and relapse‐free survival (p = 0.014) as well as the lymph node status and tumor size. In contrast, there were no significant associations between overexpression of cyclinD1 and clinical outcome in the ER‐positive subgroup. According to Coxs multivariate analysis in the ER‐negative subgroup, overexpression of cyclinD1 had the most significant effect on overall survival (p = 0.02) and relapse‐free survival (p = 0.0058), followed by nodal status and histologic grade. These findings suggest that overexpression of cyclinD1 is an independent prognostic indicator in ER‐negative breast cancer patients.

Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer

Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, Sagara Y, Sagara Y & Tanimoto A
(2011) Histopathology59, 776–780

Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study

Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Sagara Y, Sagara Y, Rai Y & Tanimoto A
(2011) Histopathology58, 608–616
Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node‐positive breast cancers: a long‐term follow‐up study

Von Recklinghausen's Disease Associated with Somatostatin‐rich Duodenal Carcinoid (Somatostatinoma), Medullary Thyroid Carcinoma and Diffuse Adrenal Medullary Hyperplasia

This report describes the concomitant occurrence of a somatostatin‐rich duodenal carcinoid, a medullary thyroid carcinoma and a diffuse adrenal medullary hyperplasia in a patient with von Recklinghausens disease. A 50‐year‐old Japanese man died from lung metastasis of a malignant schwannoma. In addition to extensive viscero‐cutaneous neurofibromatosis, two different types of neuroendocrine tumors were found in the duodenum and thyroid gland at autopsy. The duodenal tumor, which was located in the second portion, showed the histologic appearance of a carcinoid tumor with glandular differentiation and psammoma‐bodies. Immunohistochemically the tumor cells were intensely positive for somatostatin. The thyroid tumor was composed of nests of tumor cells arranged in an endocrine pattern, and showed immunoreactivity for calcitonin. A review of the literature revealed no previously reported case of concomitant occurrence of duodenal somatostatinoma and medullary thyroid carcinoma in a single patient with von Recklinghausens disease. Morphometric analysis of adrenal glands disclosed the presence of diffuse medullary hyperplasia. Thus, the present case exhibited a similarity in some respects with multiple endocrine neoplasia (MEN) syndrome, Type Ila or IIb.

Expression of wild-type estrogen receptor β protein in human breast cancer: Specific correlation with HER2/neu overexpression

Expression of estrogen receptor β (ERβ) protein in human breast cancer and correlation with clinicopathological factors have been reported by many investigators, but many of them used ERβ antibodies that react with both wild‐type ERβ (ERβwt) and splicing variant isoform. Therefore, the frequency and correlation with clinicopathological factors of ERβwt expression remain to be established. In the present study a monoclonal antibody EMR02, specific for ERβwt, was used in formalin‐fixed paraffin‐embedded sections from 225 female primary breast cancer patients diagnosed as having invasive ductal carcinoma. Expression of ERα, progesterone receptor (PgR) and HER2/neu were also investigated by immunohistochemistry. For ERβwt, ERα and PgR, positivity was defined as nuclear staining in >10% of the cancer cells. HER2/neu overexpression was defined as a Hercep test score 3+. Positivity for ERβwt, ERα, PgR and HER2/neu overexpression was 55%, 74%, 61% and 25%, respectively. The expression of ERβwt had a positive correlation with ERα (P = 0.018) and PgR (P = 0.02). There was significant positive correlation between ERβwt expression and HER2/neu overexpression (P < 0.0001). According to multivariate logistic regression analysis the most significant association was between ERβwt expression and HER2/neu overexpression (P < 0.0001). These results suggest that clinical significances of ERβwt expression in human breast cancer patients may be more complex.

Maspin expression is frequent and correlates with basal markers in triple-negative breast cancer.

BackgroundMaspin is a unique member of the serine protease inhibitor superfamily and its expression is found in myoepithelial cells of normal mammary glands; therefore, it has been considered to be a myoepithelial marker. We previously reported that maspin was frequently expressed in biologically aggressive breast cancers. In turn, triple-negative (TN) breast cancer is a subtype of tumor with aggressive clinical behavior and shows frequent expression of basal markers. We hypothesized that maspin expression may be frequent and correlate with basal rather than myoepithelial markers in TN breast cancer.MethodsParaffin-embedded 135 TN invasive ductal carcinoma tissue samples were immunohistochemically investigated using the Dako Envision+ kit and primary antibodies for maspin, basal (CK5/6, EGFR, CK14) and myoepithelial markers (p63, CD10). The correlation between maspin expression and relapse-free survival (RFS) was investigated by the log-rank test.ResultsThe positive rate for maspin was 85.9% and significantly correlated with younger age (P = 0.0015), higher histological grade (P = 0.0013), CK5/6 positivity (P < 0.0001), CK14 positivity (P = 0.0034) and the basal-like subtype defined by CK5/6, EGFR and CK14 positivity (P = 0.013). The positive rates for CK5/6, EGFR, CK14, CD10 and p63 were 59.2%, 48.9%, 34.1%, 17.8% and 12.6%, respectively. There was no significant correlation between maspin expression and RFS.ConclusionsThe positive rate for maspin is the highest among known basal and myoepithelial markers, and strongly correlates with basal markers in TN breast cancer. These results suggested that maspin could be a candidate for a therapeutic target for TN breast cancer.

Retractile mesenteritis of the large bowel: Report of a case and review of the literature

We report herein the case of a 46-year-old woman found to have retractile mesenteritis of the rectosigmoid colon. A review of 52 cases of retractile mesenteritis of the large bowel collected from the literature is discussed following our case report. The average age of the patients was 54.5 years and the male:female ratio was 37:15. The majority of lesions (61.5%) were located in the rectosigmoid colon, with abdominal pain, an abdominal mass, constipation, and fever being the most common symptoms. The diagnosis was only able to be made at the time of laparotomy in 90.4% of the patients. The gross appearance at surgery was characterized by a thickened, shortened, and retractile mesentery, forming nodular masses involving the appendices epiploicae of the colon. Microscopically, fibrosis, inflammatory cell infiltrations, degeneration of the fatty tissue or fat necrosis, and aggregations of lipid-laden foamy cells were observed in most patients. The mass involving the colon was resected in 59.6% of the patients, but even external or bypass colostomy demonstrated favorable results.