Yuko Sasajima

Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12–135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P=0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P=0.0003, 95% CI 3.02 – 40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21–9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.

Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

Melanoma is the most deadly tumor of the skin, and systemic therapies for the advanced stage are still limited. Recent genetic analyses have revealed the molecular diversity of melanoma and potential therapeutic targets. By screening a cohort of 142 primary nonepithelial tumors, we discovered that about 10% of melanoma cases (4/39) harbored an IDH1 or IDH2 mutation. These mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant, acquired increased colony-forming and in vivo growth activities and showed enhanced activation of the MAPK and STAT3 pathways. Genome-wide gene expression profiling demonstrated that mutant IDH1 affected the expression of a set of genes. Especially, it caused the induction of growth-related transcriptional regulators (Jun, N-myc, Atf3) and the reduction of Rassf1 and two dehydrogenase genes (Dhrs1 and Adh5), which may be involved in the carcinogenesis of IDH1-mutated tumors. Our analyses demonstrate that IDH1 mutation works with other oncogenic mutations and could contribute to the metastasis in melanoma.

Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma.

Cap43 is a nickel- and calcium-inducible gene that plays important roles in the primary growth of malignant tumors, as well as in invasion and metastasis, most likely through its ability to induce cellular differentiation. This study investigated associations of Cap43 expression with angiogenesis and other clinicopathological factors in cervical adenocarcinoma. The clinical records of 100 women who underwent surgery for cervical adenocarcinoma were reviewed retrospectively. Microvessel density and the expression of Cap43 and VEGF in the surgical specimens were evaluated immunohistochemically. The Cap43 expression level was significantly associated with angiogenesis, tumor diameter, stromal invasion, lymphovascular space invasion, lymph node metastasis, and histopathological differentiation. Kaplan-Meier analysis showed a significant association between the Cap43 expression level and survival: high Cap43 expression was related to poor survival. Our results suggest that increased expression of Cap43 is associated with angiogenesis and may be a poor prognostic indicator in women with cervical adenocarcinoma.

Radical hysterectomy for FIGO stage I-IIB adenocarcinoma of the uterine cervix.

A retrospective analysis was carried out to identify risk factors for survival and relapse in patients with FIGO stage I–IIB cervical adenocarcinoma (AC), who underwent radical hysterectomy, and to compare outcome and spread pattern with those of squamous cell carcinoma (SCC). One hundred and twenty-three FIGO stage I–IIB patients with AC and 455 patients with SCC, who all underwent primary radical hysterectomy, were reviewed. Among the patients with AC, Cox model identified tumour size (95% CI: 1.35–30.71) and node metastasis (95% CI: 5.09–53.44) as independent prognostic factors for survival, and infiltration to vagina (95% CI: 1.15–5.76) and node metastasis (95% CI: 6.39–58.87) as independent prognostic factors for relapse. No significant difference was found in survival or relapse between the AC and SCC groups, after adjusting for other clinicopathological characteristics using Cox model. No significant difference was found in the positive rates of lymph nodes or location of initial failure sites between the two groups, but ovarian metastatic rate was significantly higher in patients with pathologic stage IIB AC (P=0.02). Positive node is a common independent prognostic factor for survival and relapse of patients with AC. FIGO stage I–IIB patients with AC or SCC, who underwent radical hysterectomy, have similar prognosis and spread pattern, but different ovarian metastasis rates.

Reappraisal of synchronous and multifocal mucinous lesions of the female genital tract: a close association with gastric metaplasia

Aims:  To describe the gastric phenotype of synchronous mucinous metaplasia and neoplasms of the female genital tract (SMMN–FGT).

Metaplastic carcinoma of the breast

The purposes of this study were to investigate whether the biological characteristics or outcomes of patients with metaplastic carcinoma, invasive ductal carcinoma, or invasive lobular carcinoma of the breast differ; to determine whether the metaplastic carcinoma subtypes have similar malignant potentials; and to identify accurate predictors of outcome in patients with metaplastic carcinoma. The subject comprised 6137 invasive ductal carcinoma patients, 301 invasive lobular carcinoma patients, and 46 metaplastic carcinoma patients of the breast. The metaplastic carcinomas were classified according to the World Health Organization classification. Multivariate analyses clearly demonstrated that the metaplastic carcinoma patients had a significantly poorer outcome than the invasive ductal carcinoma patients or the invasive lobular carcinoma patients independent of the nodal status or age not exceeding 39 years, whereas patients with triple-negative metaplastic carcinomas or triple-negative invasive lobular carcinomas had a poorer outcome than those with triple-negative invasive ductal carcinomas. Although no significant differences in clinical outcome were observed among the metaplastic carcinoma subtypes in multivariate analyses, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant outcome predictors for metaplastic carcinoma patients. In conclusion, the results of this study clearly demonstrated that metaplastic carcinoma is more aggressive than invasive ductal carcinoma or invasive lobular carcinoma. Although the metaplastic carcinoma subtypes had no prognostic significance, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant predictors of outcome among metaplastic carcinoma patients.

Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Coxs univariate and multivariate analyses. For all patients, the 5‐year recurrence‐free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS. (Cancer Sci 2012; 103: 926–932)

Ki-1 (CD30) Positive anaplastic large cell lymphoma of T-cell phenotype developing in association with long-standing tuberculous pyothorax: Report of a case with detection of Epstein-Barr virus genome in the tumor cells

We report a case of CD30 positive anaplastic large cell lymphoma of T-cell phenotype developing in association with long-standing tuberculous pyothorax. Phenotypic analysis showed CD1a-, CD2+, CD3+, CD4+, CD5-, CD8-, CD10-, CD19-, CD20 +/-, CD21-, CD25-, CD56-, T-cell receptor (TCR) alpha/beta antigens-, and HLA-DR+ phenotype. Neither rearrangement of TCR beta and gamma chain genes or of immunoglobulin heavy chain gene was detected in DNA extract from fresh material. The lymphoma cells were also shown to express the latent membrane protein-1 and the Epstein-Barr virus (EBV)-encoded nuclear antigen-2 by immunohistochemistry and EBV-encoded small RNAs by in situ hybridization.

Reproducible and clinically meaningful differential diagnosis is possible between lobular endocervical glandular hyperplasia and 'adenoma malignum' based on common histopathological criteria

The aim of the present study was to determine if the differential diagnosis between lobular endocervical glandular hyperplasia (LEGH) and minimal deviation adenocarcinoma (MDA), or ‘adenoma malignum’, is reproducible when clear criteria for these two lesions are given. A total of 44 proliferative endocervical glandular lesions were collected, for which differential diagnosis from MDA was considered to be necessary. Seven observers independently classified these 44 lesions into LEGH, LEGH with adenocarcinoma in situ (AIS), MDA, or common cervical adenocarcinoma, according to the following criteria: LEGH was non‐invasive proliferation of endocervical glandular cells without any obvious adenocarcinoma component. MDA was very well‐differentiated endocervical‐type mucinous adenocarcinoma composed mostly of LEGH‐looking glands but containing the component of obviously invasive adenocarcinoma. LEGH with AIS was defined as continuous coexistence of LEGH and AIS. Among these four diagnostic categories, the interobserver agreement level was substantial (κ = 0.618). The level increased to almost perfect (κ = 0.928) between the group of non‐invasive lesions consisting of LEGH and LEGH with AIS and the other group of invasive lesions comprising MDA and common adenocarcinoma. When the modal diagnosis was adopted as the final diagnosis for individual lesions, the 5 year survival rate of patients after surgery was 100% for the non‐invasive lesions but only 54% for the invasive lesions (P < 0.01). It is clearly shown that reproducible differential diagnosis is possible between LEGH, LEGH with AIS, and MDA and that such a differentiation is clinically meaningful.

p53 expression in tumor-stromal fibroblasts is closely associated with the nodal metastasis and outcome of patients with invasive ductal carcinoma who received neoadjuvant therapy

The purpose of this study was to determine whether p53 immunoreactivity in tumor-stromal fibroblasts assessed by the Allred scoring system in biopsy specimens obtained before neoadjuvant therapy and assessed in surgical specimens obtained after neoadjuvant therapy is significantly associated with nodal metastasis by invasive ductal carcinoma and with the outcome of 318 patients with invasive ductal carcinoma who received neoadjuvant therapy, according to UICC pathologic TNM stage, in multivariate analyses with well-known clinicopathologic factors. The Allred scores for p53 in tumor-stromal fibroblasts in the surgical specimens were significantly associated with the presence of nodal metastasis. The Allred scores for p53 in the tumor-stromal fibroblasts of biopsy and surgical specimens were a very important outcome predictive factor for patients who received neoadjuvant therapy, independent of UICC pathologic TNM status, but the outcome predictive power of the Allred scores for p53 in tumor-stromal fibroblasts assessed in the surgical specimens was superior to that of the Allred scores for p53 in tumor-stromal fibroblasts in the biopsy specimens. The results indicated a close association between p53 protein expression in tumor-stromal fibroblasts, especially in surgical specimens, and both the presence of nodal metastasis and the outcome of invasive ductal carcinoma patients who received neoadjuvant therapy.