Hiroshi Sonoue

c-erbB-2 oncoprotein expression related to chemoradioresistance in esophageal squamous cell carcinoma

PURPOSE Esophageal carcinoma is a challenging target for radiotherapy. To improve treatment efficacy, an investigation of a predictive factor is desirable. In this study, we evaluated the significance of apoptosis and immunohistochemical staining for p53, Ki-67, c-erbB-2 (HER-2/neu), Ku (p70/p80), and DNA-PKcs for predictive markers of the responsiveness to chemoradiotherapy in esophageal squamous cell carcinoma. MATERIALS AND METHODS This retrospective analysis consisted of 34 patients with esophageal squamous cell carcinoma in whom tumor biopsy was performed before treatment. They were divided into chemoradiosensitive (n = 13) and chemoradioresistant (n = 21) groups according to the tumor response evaluated at a total radiation dose of 40 Gy. The biopsy samples were examined with immunohistochemical staining for various factors and with an in situ nick end labeling method for apoptosis. The examined data were compared between the two groups. RESULTS The difference in the Ki-67, p53, Ku (p70/p80), DNA-PKcs labeling indexes and the apoptosis index in tumor cells between the chemoradiosensitive and chemoradioresistant groups was not statistically significant. The expression of c-erbB-2 oncoprotein was statistically significant in the chemoradioresistant group (p = 0.02), although it did not correlate with survival. CONCLUSIONS c-erbB-2 immunostaining is useful for the prediction of chemoradioresistance in esophageal squamous cell carcinoma.

Abnormality of autophagic function and cathepsin expression in the liver from patients with non‐alcoholic fatty liver disease

Recent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non‐alcoholic fatty liver disease (NAFLD).

Grading system of lymphatic invasion according to D2-40 immunostaining is useful for the prediction of nodal metastasis in squamous cell carcinoma of the uterine cervix

Aims To determine the relationship between lymphatic invasion detected by D2‐40 immunostaining and nodal metastasis in squamous cell carcinoma (SCC) of the cervix.

Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia.

Objectives: To examine aberrations and differences of cell cycle regulatory proteins between intraductal papillary-mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasias (PanINs). Methods: In total, 47 IPMN lesions and 42 PanIN lesions were obtained from 26 patients with IPMN and 16 patients who underwent pancreatic surgery for invasive pancreatic ductal cancer or other diseases. They were subjected to conventional hematoxylin-eosin staining and immunostaining for p16INK4A and p53. The percentages of immunohistochemical positivity or negativity were compared between IPMN and PanIN, in accordance with the same histological grade of atypia. The Ki-67 labeling index was also counted in each lesion. Results: Either the loss of p16INK4A expression or the overexpression of p53 was much more frequently observed among PanIN-3 than among carcinoma in situ in IPMN (P = 0.046 and 0.008, respectively). The Ki-67 labeling index was correlated with the histological grades of both PanINs and IPMNs (P = 0.0001 and P = 0.0001, respectively). Conclusions: There are different immunohistochemical expression patterns of p16INK4A and p53 between IPMNs and PanINs. These may substantiate their different genetic progressions to invasive carcinoma.Abbreviations: IPMN - intraductal papillary-mucinous neoplasia, PanIN - pancreatic intraepithelial neoplasia

Lymphatic invasion according to D2-40 immunostaining is a strong predictor of nodal metastasis in superficial squamous cell carcinoma of the esophagus: Algorithm for risk of nodal metastasis based on lymphatic invasion

In squamous cell carcinoma (SCC) of the esophagus, D2‐40 immunostaining has recently been used to detect lymphatic invasion, but invasion detected using D2‐40 immunostaining for a predictor of nodal metastasis was controversial. Therefore, the usefulness of detecting lymphatic invasion by D2‐40 immunostaining as a predictor of nodal metastasis was examined in superficial (mucosal and submucosal) SCC of the esophagus. A total of 115 superficial SCC of the esophagus were examined on immunohistochemistry using D2‐40. It was found that lymphatic invasion demonstrated on D2‐40 immunostaining was mainly detected in the lamina propria mucosa. Lymphatic invasion was found in 37 cases and the invasion detected in the entire tumor tissue was statistically correlated with nodal metastasis. Based on the lymphatic invasion according to D2‐40 immunostaining, an algorithm was devised for the risk (low, intermediate and high) of nodal metastases in superficial SCC in the esophagus. In conclusion, the detection of lymphatic invasion on D2‐40 immunostaining in tumor tissue is a strong predictor for nodal metastasis in superficial SCC of the esophagus. Lymphatic invasion was found mainly in the lamia propria mucosa, thus the devised algorithm is useful for determining the optimal treatment strategy after endoscopic mucosal resection for esophageal SCC.

Intraductal Spread of Pancreatic Cancer

Background: Invasive ductal adenocarcinoma of the pancreas (IDAP) also spreads through the pancreatic ductal tree. The aim of this study was to clarify the clinicopathologic features of IDAP with intraductal spread. Methods: We studied the intraductal spread of IDAP and its correlation with clinicopathologic parameters in a surgical series of 54 patients. The pancreatic ducts were analyzed by confirmation of mural elastic fibers with elastica van Gieson stain. Results: Intraductal spread of carcinoma was identified in 37 patients (69%). Such spread was frequent in well-differentiated IDAP (93%), and the number of intraductal carcinoma foci was correlated with the grade of tumor differentiation (p < 0.001). The large branch ducts were the main route of intraductal spread (64.1%). The proliferation index, evaluated using Ki67, was lower in the intraductal carcinoma components than in the associated infiltrating carcinoma components (p < 0.001). The presence or absence of intraductal spread was not correlated with age, sex, tumor location, tumor size, or stage. IDAP with intraductal spread showed a tendency, although it was not significant (p = 0.092), to be associated with longer survival compared with IDAP without intraductal spread. Conclusion: IDAP, especially of the well-differentiated type, has a tendency to spread intraductally. The difference between the Ki67 labeling indexes in the intraductal and associated infiltrating carcinoma components suggests that these components show different biological behaviors.

Prognostic significance of the infiltrative pattern invasion in endometrioid adenocarcinoma of the endometrium

The prognostic significance of the invasive type of carcinoma cells in endometrial carcinoma is not defined. We evaluated the prognostic significance of the invasive type, as well as the immunostains of p53, c‐erbB‐2, Ki‐67 antigen and MDM2 in endometrial endometrioid adenocarcinoma. This prospective analysis comprised 112 patients with endometrioid adenocarcinoma of the uterine corpus who had undergone surgery and were traced for more than 5 years after the operation. They were divided into re‐currence (16 patients) and non‐recurrence (96 patients) groups. The invasive type of carcinoma cells was divided into expansile, mixed (expansile and infiltrative) and infiltrative pattern. The difference in the invasive type (P < 0.001) and p53 expression (P = 0.004) between the recurrence and non‐recurrence groups was significant in the univariate analysis. Moreover, the invasive type was significant in the multivariate analysis (P = 0.004). In contrast, the difference in MDM2 expression, c‐erbB‐2 expression and the Ki‐67 labeling index in both groups was not significant in the univariate analysis. The infiltrative pattern of the invasive type (P < 0.001) and p53 expression (P = 0.043) were significantly related to a poor prognosis in the Kaplan–Meier method using the log–rank test. In conclusion, the current study indicated that the infiltrative pattern of the carcinoma cells is a predictor for poor prognosis in endometrioid adenocarcinoma in the uterine corpus. It was also indicated that p53 immunostains are useful as a predictor, but Ki‐67 antigen, c‐erbB‐2 and MDM2 stains are not.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases

Background:FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression.Methods:Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments.Results:FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome.Conclusions:Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Lymphatic invasion according to D2-40 immunostaining is a predictor of nodal metastasis in endometrioid adenocarcinoma of the uterine corpus

In endometrioid adenocarcinoma of the uterine corpus, nodal metastasis is related to prognosis. D2‐40 immunostaining has recently been used to detect lymphatic invasion, but a study of D2‐40 immunostaining for endometrioid adenocarcinoma of the uterine corpus has not been published. Therefore, as a predictor of nodal metastasis in endometrioid adenocarcinoma of the uterine corpus, the detection of lymphatic invasion on D2‐40 immunostaining and lymphovascular invasion on HE stain was compared. A total of 104 cases of invasive endometrioid adenocarcinoma of the uterine corpus, in which the tumor was located in the uterus, were examined on immunohistochemistry using D2‐40. In 20 cases there was lymphatic invasion according to D2‐40 immunostaining, and the lymphatic invasion was well detected on D2‐40 immunostaining. Nodal metastasis was present in 11 cases. Both lymphatic invasion on D2‐40 immunostaining and lymphovascular invasion on HE stain were statistically correlated with nodal metastasis, but the evaluation of lymphatic invasion on D2‐40 immunostaining was more accurate than detection of lymphovascular invasion using HE stain, in the current and previous studies, for the prediction of nodal metastasis. In conclusion, lymphatic invasion demonstrated on D2‐40 immunostaining is very useful as a predictor for nodal metastasis in endometrioid adenocarcinoma of uterine corpus.

Subepithelial extension of squamous cell carcinoma in the esophagus: Histopathological study using D2‐40 immunostaining for 108 superficial carcinomas

Squamous cell carcinoma (SCC) of the esophagus occasionally produces subepithelial extension (SEE) in the stroma below the non‐cancerous epithelium. Little information on SEE has been obtained, therefore the purpose of the present study was to carry out a clinicopathological study using D2‐40 immunostaining in 108 cases of superficial (mucosal and submucosal) SCC of the esophagus. SEE occurred in 24 cases (22.2%). The SEE was present in both mucosa and submucosa in 19 cases, but in five cases SEE was located in the mucosa. Lymphatic invasion of tumor cells was well determined on D2‐40 immunostaining. In the SEE group lymphatic invasion was found in 15 cases, and in two cases there was lymphatic invasion in the lamina propria mucosa of the edge of SEE. In the SEE group 23 (95.8%) had infiltrative growth of tumor cells. Lymphatic invasion and growth pattern of tumor cells were statistically correlated with SEE. Lymph node metastases were found in 48 cases, but SEE was not correlated with nodal metastases statistically. In conclusion, esophageal SCC produces SEE from the early stage by infiltrative growth and lymphatic invasion of tumor cells. The detection of lymphatic invasion on D2‐40 immunostaining in the mucosal edge of SEE is useful for evaluation of endoscopic mucosal resection tissue.