Fumitaka Saito

Prognostic significance of CD169‐positive lymph node sinus macrophages in patients with endometrial carcinoma

Lymph node (LN) macrophages play critical roles in anti‐tumor immunity, which develops via the activation of cytotoxic T cells (CTL) and NK cells. The present study aims to determine the prognostic significance of CD169+ LN macrophages in patients with endometrial carcinoma (EC). The number of CD169+ cells or the CD169+‐to‐CD68+ macrophage ratio in regional LN (RLN), and the number of CD8+ CTL or CD57+ NK cells in tumor tissues were investigated by immunohistochemistry in paraffin‐embedded tissue samples from 79 patients with EC. A high density of CD169+ cells in the RLN of patients with EC was correlated with an early clinical stage or no LN metastasis. A high number of CD169+ cells and a high CD169+‐to‐CD68+ macrophage ratio were significantly associated with longer overall survival in EC. We also found that the density of CD169+ macrophages was positively correlated with the number of CD8+ CTL and CD57+ NK cells that infiltrated into tumor tissues. A high density of CD57+ cells in EC tissues was associated with a better prognosis, while a high density of CD8+ cells was not linked to an altered prognosis. The present study showed that the density of CD169+ macrophages in RLN was associated with an improved prognosis in EC patients. CD169+ macrophages in RLN might represent a useful marker for assessing clinical prognoses and monitoring anti‐tumor immunity in patients with EC.

Endometrioid adenocarcinoma arising in adenomyosis: elucidation by periodic magnetic resonance imaging evaluations

There are several case reports of adenocarcinomas developing within adenomyosis. However, there is no report demonstrating the natural course from adenomyosis to adenocarcinoma. We report a patient (a 41-year-old Japanese woman) who was observed every 6 months after being diagnosed with adenomyosis at our University Hospital. Although she went through menopause at age 51, she occasionally complained subsequently of abnormal genital bleeding. Eleven years after the initial diagnosis, endometrial cytology revealed the presence of malignant cells. Pelvic magnetic resonance imaging (MRI) demonstrated replacement of the adenomyotic lesion by a poorly demarcated lesion, compared to the findings on prior MRI. Consequently, we performed a modified radical hysterectomy and pelvic lymph node dissection, under a presumptive diagnosis of adenocarcinoma arising in adenomyosis. Histological diagnosis revealed an endometrioid adenocarcinoma (G3) transformed from adenomyotic epithelium, which was classified, according to the International Federation of Gynecology and Obstetrics, as stage Ic, pT1cN0M0. In this patient, periodic MRI evaluations, in conjunction with pathological examination, identified the transformation from adenomyosis to adenocarcinoma.

Mutual contribution of Pten and estrogen to endometrial carcinogenesis in a PtenloxP/loxP mouse model.

Objective: An association between estrogen and the risk of type 1 endometrial carcinoma, which shows frequent mutations in the Pten tumor suppressor gene, has consistently been found in many studies. However, such tumors usually arise in perimenopausal or postmenopausal women with decreased serum estrogen levels. This study aimed to reveal the contributions of estrogen to endometrial carcinogenesis in a mouse model of endometrial carcinoma initiated by conditional targeting of Pten. Methods: The Cre-loxP system was used to achieve Pten inactivation within mouse endometrial epithelium. We delivered a recombinant adenovirus vector expressing Cre recombinase to the endometrial cavity of the Pten loxP/loxP mice that had been ovariectomized at 10 weeks old. Mice were subcutaneously injected with 17&bgr;-estradiol (E2) or vehicle, followed by injection of the adenovirus. Two weeks after adenovirus injection, the entire endometrium was analyzed. Results: Mice that did not receive E2 injection notably developed endometrial neoplasia, complex atypical hyperplasia, or carcinoma (7/8, 87.5%). In contrast, hyperplastic but nonneoplastic endometrium was observed in E2-treated mice. In these E2-treated mice, immunohistochemistry revealed that Pten-null glandular epithelial cells clonally proliferate among the hyperplastic endometrium. Conclusions: The results of this study suggest that estrogen clonally proliferates Pten-null epithelial cells together with surrounding cells, and depletion of estrogen induces predominant growth of Pten-null cells with estrogen-independent capabilities, resulting in abnormal structure of the glandular cells and subsequent neoplasia. This phenomenon might explain why the incidence of human endometrial carcinoma increases with perimenopausal or postmenopausal status, which represents declining ovarian function. Our model mice have partially resolved the issue of endometrial Pten- and estrogen-related carcinogenesis and have potential to represent a valuable tool for developing novel therapies against this carcinoma.

Development of a mouse model for testing therapeutic agents: the anticancer effect of dienogest on endometrial neoplasms.

Abstract Objective: As the number of younger women with endometrial carcinoma has increased, fertility-sparing treatments have received more attention. Although there have been several reports on conservative treatments with progestins for endometrial carcinoma, only medroxyprogesterone acetate (MPA) is available in Japan. Dienogest has been developed as a fourth-generation progestin for treating endometriosis. Because of its high progesterone activity, its antitumor activity has attracted attention. In this study, we investigated the anticancer effect of dienogest on endometrial neoplasms using mouse model of endometrial carcinoma. Methods/materials: PtenloxP/loxP mice were injected with MPA or dienogest subcutaneously to evaluate the anticancer effect against endometrial neoplasms that developed in the mice. One week after injections, histopathological analyzes were performed. Results: Endometrial neoplasms were found in one of the eight (12.5%) mice from each group treated with either dienogest or MPA. In contrast, they were found in seven of eight (87.5%) mice not treated with progestins. Each progestin treatment showed anticancer activity against endometrial neoplasms that developed in the mice compared to those without treatment. Conclusions: Dienogest and MPA showed potent anticancer activity against endometrial neoplasms in our mouse model. The present study demonstrated that dienogest might be a useful therapeutic agent for human endometrial neoplasms.

Long-Term Outcome of Aromatase Inhibitor Therapy With Letrozole in Patients With Advanced Low-Grade Endometrial Stromal Sarcoma.

Background There has been no consensus on the indications for the treatment of advanced low-grade endometrial stromal sarcoma (LGESS), and the possible effects of hormonal treatment including progestins and aromatase inhibitors have been reported. The aim of this study was to investigate the efficacy of aromatase inhibitor therapy with letrozole for patients with residual or recurrent LGESS. Methods We retrospectively reviewed the clinical response of patients with advanced LGESS who had been treated with letrozole. We also analyzed the adverse effects after the administration of letrozole. The expression levels of estrogen receptor and aromatase in the tumors were immunohistochemically examined. Results In 5 patients who had been treated for unresectable LGESS lesions after initial or repeat surgical procedures, residual lesions in 3 patients and recurrence lesions in 2 patients were the indications for hormonal therapy with letrozole. The median duration of letrozole exposure at retrospective analysis was 53 (10–96) months. The clinical outcomes were classified as complete response in 2 patients, partial response in 1 patient, and stable disease in 2 patients. Myalgias, hot flashes, and arthralgias were not observed during the follow-up period in any patients. The median serum levels of estradiol were <5.0 (cutoff value, <0.5–11.8) pg/mL. The median age-matched bone mineral densities were 92% (79%–123%). The LGESS tissues in all 5 patients were positive for estrogen receptor and aromatase expression. Conclusions Letrozole as well as progestins could be the first choice of treatment for patients with recurrent or residual LGESS, which is difficult to resect surgically because of its efficacy and minimal adverse effects.

An Ovarian Carcinoid Tumor With Peptide YY-Positive Insular Component: A Case Report and Review of the Literature.

Ovarian carcinoid tumors are uncommon and account for 1% of all carcinoid tumors. The insular type of ovarian carcinoid tumor is common in western countries; in contrast, the strumal and trabecular types seem to be common in Asian countries. Strumal and trabecular types are associated with peptide YY (PYY) production, which may cause constipation. Here, we report the case of a 70-yr-old Japanese woman with chronic constipation who was referred to Kumamoto University Hospital because of a right adnexal mass. Imaging tests suggested that the solid mass might be malignant; therefore, abdominal total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy were performed. A subsequent histopathologic examination confirmed an insular carcinoid tumor with a trabecular component in the right ovary. Both components were positive for PYY but not for serotonin. The patient complained of diarrhea instead of constipation soon after the surgery. Because PYY-positive insular carcinoid tumor in the ovary has not been previously reported, we reviewed 19 reported cases of patients with PYY-positive ovarian carcinoid tumors. The origins, common histologic types and symptoms caused by specific peptides secreted in ovarian carcinoid tumors differ between western and Asian countries.

High-dose oral tegafur-uracil maintenance therapy in patients with uterine cervical cancer

Objective The aim of this study was to determine the efficacy and toxicity of oral administration of tegafur-uracil (UFT) at a high dose, 600 mg/day, based on the tegafur dose, against uterine cervical cancer. Methods This study consisted of a retrospective analysis. From April 1986 to March 1997, 309 patients with uterine cervical cancer were registered. Oral UFT was administered to 162 patients for maintenance therapy after an initial treatment (the UFT group). The other 147 patients were not treated with UFT (the control group). The survival rate was calculated for both groups and statistically analyzed using the log-rank test. Adverse events were compared between the UFT and control groups. Results In the UFT group, 103 patients (63.6%) received UFT for ≥90 days. The drug dose was 600 mg/day for 137 patients (84.6%) and 300 to 400 mg/day for the remainder. The overall survival rate was significantly higher in the UFT group than in the control group (p<0.05). The prognosis was particularly favorable in stage III cases, in cases of squamous cell carcinoma, and in cases that were treated by radiotherapy. The most frequent side effects were nausea/vomiting (12.2%), appetite loss (10.1%), and leukopenia/neutropenia (5.8%). Conclusion High-dose oral UFT maintenance treatment prolonged the disease-free survival and overall survival of patients with uterine cervical cancer, particularly of those with advanced disease.

Choriocarcinoma coexisting with epithelioid trophoblastic tumor of the uterine horn

Highlights • We report a choriocarcinoma coexisting with an epithelioid trophoblastic tumor.• Chemotherapy with methotrexate, etoposide, and actinomycin-D was efficacious.• Choriocarcinoma with epithelioid trophoblastic tumor may benefit from chemotherapy.

Prognostic factors and optimal therapy for stages I–II neuroendocrine carcinomas of the uterine cervix: A multi-center retrospective study

PURPOSE We aimed to determine appropriate treatment guidelines for patients with stages I-II high-grade neuroendocrine carcinomas (HGNEC) of the uterine cervix in a multicenter retrospective study. PATIENTS AND METHODS We reviewed the clinicopathological features and prognoses of 93 patients with HGNEC of International Federation of Gynecology and Obstetrics (FIGO) stages I and II. All patients were diagnosed with HGNEC by central pathological review. RESULTS The median overall survival (OS) and disease-free survival (DFS) were 111.3months and 47.4months, respectively. Eighty-eight patients underwent radical surgery, and five had definitive radiotherapy. The hazard ratio (HR) for death after definitive radiotherapy to death after radical surgery was 4.74 (95% confidence interval [CI], 1.01-15.90). Of the surgery group, 18 received neoadjuvant chemotherapy. Pathological prognostic factors and optimal adjuvant therapies were evaluated for the 70 patients. Forty-one patients received adjuvant chemotherapy with etoposide-platinum (EP) or irinotecan-platinum (CPT-P). Multivariate analyses identified the invasion of lymphovascular spaces as a significant prognostic factor for both OS and DFS. Pelvic lymph node metastasis was also a prognostic factor for DFS. Adjuvant chemotherapy with an EP or CPT-P regimen appeared to improve DFS (HR=0.27, 95% CI, 0.10-0.69). A trend toward improved OS was also observed, but was not statistically significant (HR=0.39, 95% CI, 0.15-1.01). CONCLUSION Radical surgery followed by adjuvant chemotherapy with an EP or CPT-P regimen was optimal treatment for stages I and II HGNEC of the uterine cervix.

Polycystic ovary syndrome: early diagnosis and intervention are necessary for fertility preservation in young women with endometrial cancer under 35 years of age

Polycystic ovary syndrome (PCOS) is a significant risk factor for premenopausal endometrial cancer (EC) and/or atypical endometrial hyperplasia (AEH). The aim was to elucidate the clinical background and detailed menstrual history of EC and/or AEH in young women with PCOS.