Yuko Shiroyama

Increased MCL–1 Expression Is Associated with Poor Prognosis in Ovarian Carcinomas

To investigate the potential role of the BCL–2 gene family (BAX, BCL–2, MCL–1, and BCL‐XL) in ovarian cancer development and progression, mRNA expression levels of these genes were measured using semi‐quantitative PCR in epithelial ovarian tumor tissues and normal ovaries. The immunohistochemical expression of MCL–1 in ovarian tumors was also examined. The expression levels of BAX and MCL–1 mRNA were significantly higher in ovarian cancers and in adenomas than in normal ovaries (P<0.05). In contrast, the BCL–2 mRNA expression level in ovarian cancers was significantly lower than in ovarian adenomas and in normal ovaries (P<0.05). Expression of BCL‐XL mRNA was no different between normal ovaries and ovarian tumors. Log‐rank testing showed that low BAX mRNA expression and high MCL–1 mRNA expression significantly correlate with poor survival for patients with stage III ovarian carcinomas (BAX, P=0.05; MCL–1, P=0.02). Immunohistochemical analysis showed that diffuse‐positive expression of MCL–1 protein in mucinous carcinomas was significantly higher than in mucinous low malignant potential (LMP) tumors (P=0.03). In ovarian cancer cases, diffuse‐positive expression of MCL–1 protein significantly correlates with advanced clinical stage, high histologic grade, and poor survival (stage, P<0.01; grade, P=0.01; survival, P=0.01). These results suggest that increased MCL–1 expression may play an important role in replacing the functions of increased BAX and decreased BCL–2 in ovarian carcinoma cells, thereby promoting cell survival, and resulting in a poor prognosis for patients with ovarian cancer.

Cyclin E mRNA overexpression in epithelial ovarian cancers: inverse correlation with p53 protein accumulation.

Objective: We investigated the relationship between cyclin E mRNA overexpression and p53 protein accumulation in epithelial ovarian cancers. Methods: mRNA was isolated and cDNA was prepared from 36 epithelial ovarian tumors (three adenomas, three low malignant potential tumors, and 30 carcinomas), and six normal ovaries. The cyclin E mRNA expression levels relative to an internal control, β-tubulin, were determined by semiquantitative polymerase chain reaction (PCR). Cyclin E and p53 protein expression in ovarian cancer tissues were examined by immunohistochemistry using the same series of samples. Fisher exact test of significance and an unpaired t test were used for statistical analysis. Results: Considerable levels of cyclin E mRNA were detected in all normal ovaries and ovarian tumor samples examined by semiquantitative PCR amplification. mRNA levels of cyclin E were significantly higher in nine of 30 (30%) ovarian cancers compared with those in normal ovaries. The immunohistochemical expression of cyclin E protein was confirmed in the nuclei of tumor cells in 13 of 30 (43%) ovarian cancers. p53 protein accumulation was detected in 12 of 30 (40%) ovarian cancers examined. There was a significant inverse correlation between cyclin E mRNA overexpression and p53 protein accumulation (P <.01, Fisher exact test). Conclusions: Cyclin E mRNA overexpression frequently occurs in ovarian cancers without p53 protein accumulation. Cyclin E might have an important effect on the development of a limited number of ovarian cancers.

Evaluation of DNA Mismatch Repair Protein Expression as a Preliminary Screening for Lynch Syndrome in Young Japanese Women with Endometrial Cancer

Background: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant cancer syndrome. There is an urgent need to identify patients with Lynch syndrome among patients with endometrial cancer. We aimed to evaluate the efficacy of measuring DNA mismatch repair (MMR) expression in young Japanese endometrial cancer patients to differentiate sporadic and Lynch syndrome-associated tumors. Methods: In a retrospective analysis of 50-year-old or younger endometrial cancer patients, 106 tumors were evaluated for MSH2, MSH6, PMS2, and MLH1 expression by immunohistochemistry. Samples lacking MLH1 were further examined by real-time PCR to evaluate hypermethylation of the MLH1 promoter. Clinical characteristics of patients with suspected Lynch syndrome were then evaluated. Results: Among the 106 samples, 25 (23.6%) had reduced MMR protein expression; MLH1, MSH2 and MSH6 staining was negative in 14, 6 and 5 cases, respectively, while no samples were negative for PMS2. Among the 14 cases lacking MLH1 staining, 10 were found to be associated with MLH1 promoter hypermethylation. Therefore, 15 (14.2%) cases of suspected Lynch syndrome-associated endometrial cancer were found. These patients presented with a significantly lower body mass index and had more first-degree relatives diagnosed with a Lynch syndromeassociated cancer. Our cohort included three Lynch syndrome patients with known mutations, and tumor samples from these patients showed an absence of the specific MMR protein that was mutated. Conclusions: Our results demonstrate that immunohistochemical analysis of tumor samples for MMR protein expression can identify patients with Lynch syndrome. With early detection, colorectal cancer outcomes might be drastically improved.

A case of uterine corpus large cell neuroendocrine carcinoma showing prominent myometrial invasion without any macroscopically clear tumor formation

Large cell neuroendocrine carcinoma (LCNEC) arising in the uterine corpus is a very rare. Here, we report our experience with a primary LCNEC in the uterine corpus that showed prominent myometrial invasion without exhibiting any macroscopically distinct tumor formation in the uterine cavity. The patient was a 54-year-old woman. She had a past medical history of right breast cancer and was referred to our department with irregular genital bleeding, elevated serum carcinoembryonic antigen in periodic medical examinations and computed tomography (CT) findings of uterine cavity dilation. Endometrial biopsy suggested a poorly differentiated tumor. Although magnetic resonance imaging (MRI) showed hematometra-like findings in the uterine cavity, it did not indicate any clear endometrial lesion. The myometrium was unequally thickened, and the entire muscle layer showed a high signal intensity on diffusion-weighted images. Fluorine-18-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) showed strong FDG accumulation in the whole uterus, and on the bottom of the uterus, there was a ring-shaped accumulation mainly in the muscle layer. The postoperative resected specimen did not show any tumor formation in the uterine cavity, whereas the myometrium was hard and thickened, and colored white overall. Histopathological examination revealed prominent myometrial invasion in most layers, cervical stromal invasion and pelvic lymph node metastasis. The diagnosis was a LCNEC of the uterine corpus, at FIGO stage IIIC1 and pT2N1M0. With these patients, we found that functional metabolic images, such as MRI diffusion-weighted images and FDG-PET/CT, were useful in identifying the lesion. Preoperatively, when a poorly differentiated tumor is estimated and characteristic myometrial invasion is suspected, the possibility of LCNEC should be considered.

A case of ependymoma arising from the peritoneum

Ependymoma arising from the peritoneum is extremely rare. We present the case of a 23-year-old woman who underwent urgent laparoscopic surgery because of a pelvic mass and intraperitoneal bleeding. Although peritoneal carcinoma was suspected, pathological re-examination revealed ependymoma with a perivascular pseudorosette and positive for glial fibrillary acidic protein. Residual tumor extraction indicated that the ependymoma had developed from the peritoneum. This case highlights the need to consider ependymoma as a potential diagnosis in young women with suspected ovarian or peritoneal cancer.

Clinical significance of peritoneal cytology including cell block method and immunohistochemical analysis in pretherapeutic diagnosis of histological subtype for excluding clear cell and mucinous adenocarcinoma from eligibility for neoadjuvant chemotherapy

16566 Background: Several clinical trials of neoadjuvant chemotherapy for advanced ovarian cancer have been conducted. However, clear cell and mucinous adenocarcinoma should be excluded from the el...