Hitoshi Hareyama

A clinical and pathologic study on para‐aortic lymph node metastasis in endometrial carcinoma

Recent studies have shown that poor survival for patients with early endometrial cancer was related to the extrapelvic spread of the cancer. The purpose of this study was to evaluate the correlation between para‐aortic lymph node (PAN) metastasis and histopathologic findings and to assess the clinical utility of identifying PAN metastasis of endometrial carcinoma.

Prognostic significance of serous and clear cell adenocarcinoma in surgically staged endometrial carcinoma

Background. The serous adenocarcinoma (SA) and clear cell adenocarcinoma (CCA) of endometrium have been shown to be associated with high relapse rate and poor survival. It is not clear whether prognostic significance of these specific cell types of tumor is independent of retroperitoneal lymph node metastasis and other histopathologic prognostic factors in endometrial carcinoma.

Bcl-2 expression and prognosis of patients with endometrial carcinoma.

Bcl‐2 protein inhibits apoptosis, reduces the requirement for growth factors, and thereby extends the survival of cells. Recent findings of Bcl‐2 in several solid tumors suggest that it might contribute to the genesis of some types of cancer. Over‐expression of Bcl‐2 might play a role in carcinogenesis and malignant progression of endometrial carcinoma. The aims of this study were to determine Bcl‐2 expression in endometrial carcinoma in relation to other histopathologic prognostic factors, and to test its prognostic significance in patients with endometrial carcinoma. A total of 61 endometrioid‐type endometrial carcinomas were immunohistochemically investigated for Bcl‐2 expression on cryostat sections. Bcl‐2 localization was observed in cytoplasm in 18 tumors, in nucleus in 27 tumors, or in both in 5 tumors. In 11 tumors, Bcl‐2 was observed neither in cytoplasm nor in nucleus. There was not a statistically significant relationship between grade of tumor and Bcl‐2 expression. Cytoplasmic Bcl‐2 became less frequently expressed as the tumor invaded the myometrium deeper (p < 0.025). Retroperitoneal lymph‐node dissection was performed in 57 patients. Multiple‐regression analysis showed that lymph‐vascular space invasion and nuclear expression of Bcl‐2 were correlated to pelvic lymph‐node metastasis (p < 0.0001 and <0.05 respectively). Univariate Cox regression analysis revealed that nuclear Bcl‐2 expression was associated with shorter survival (p < 0.05) than that of patients with cytoplasmic Bcl‐2 expression. Pelvic node metastasis was a significant prognostic factor for patients who underwent systematic retroperitoneal lymph‐node dissection. Cox multivariate‐regression analysis revealed that pelvic node metastasis and cervical invasion were the most important prognostic factors in this series of patients. When the analysis was made after exclusion of pelvic node metastasis, histologic grade (hazard ratio = 2.4), cervical invasion (hazard ratio = 3.7) and nuclear Bcl‐2 expression (hazard ratio = 11.5) were shown to be significant predictors of survival of the patients. These results indicate that aberrant Bcl‐2 expression might be involved in malignant progression of endometrioid‐type endometrial carcinoma. Site of Bcl‐2 localization may be an important predictor of prognosis for patients with endometrioid‐type endometrial carcinoma. Int. J. Cancer (Pred. Oncol.) 79:153–158, 1998.© 1998 Wiley‐Liss, Inc.

Prevalence, classification, and risk factors for postoperative lower extremity lymphedema in women with gynecologic malignancies: a retrospective study.

Objective Lower extremity lymphedema (LEL) is a major long-term complication of radical surgery. We aimed to estimate the incidence and grading of LEL in women who underwent lymphadenectomy and to evaluate risk factors associated with LEL. Materials and Methods We retrospectively reviewed 358 patients with cervical, endometrial, and ovarian cancer who underwent transabdominal complete systematic pelvic and para-aortic lymphadenectomy between 1997 and 2011. Lower extremity lymphedema was graded according to criteria of the International Society of Lymphology. Incidence of LEL and its correlation with various clinical characteristics were investigated using Kaplan-Meier survival and Cox proportional hazards methods. Results Overall incidence of LEL was 21.8% (stage 1, 60%; stage 2, 32%; and stage 3, 8%). Cumulative incidence increased with observation period: 12.9% at 1 year, 20.3% at 5 years, and 25.4% at 10 years. Age, cancer type, stage (International Federation of Gynecology and Obstetrics), body mass index, hysterectomy type, lymphocyst formation, lymph node metastasis, and chemotherapy were not associated with LEL. Multivariate analysis confirmed that removal of circumflex iliac lymph nodes (hazard ratio [HR], 4.28; 95% confidence interval [CI], 2.09–8.77; P < 0.0001), cellulitis (HR, 3.48; 95% CI, 2.03–5.98; P < 0.0001), and number of removed lymph nodes (HR, 0.99; 95% CI, 0.98–0.99; P = 0.038) were independent risk factors for LEL. Conclusions Postoperative LEL incidence increased over time. The results of the present study showed a significant correlation with removal of circumflex iliac lymph nodes and cellulitis with the incidence of LEL. Multicenter or prospective studies are required to clarify treatment efficacies.

Para-aortic lymph node metastasis in relation to serum CA 125 levels and nuclear grade in endometrial carcinoma.

Background. To investigate the relationship between preoperative serum CA 125 levels and para‐aortic lymph node (PAN) metastasis as determined by systematic pelvic and para‐aortic lymph node dissection in endometrial carcinoma.

Cox multivariate regression models for estimating prognosis of patients with endometrioid adenocarcinoma of the uterine corpus who underwent thorough surgical staging

The International Federation of Gynecology and Obstetrics (FIGO) adopted surgical staging criteria in 1988. Many studies have shown that histologic grade, nuclear grade, lymph‐vascular space invasion and cell type are also important predictors of survival. It has not been clarified, however, how to integrate these histopathologic variables into the process of estimating individual prognosis. We performed Cox multivariate regression analysis to create models that incorporate various histopathologic factors for estimating the prognoses of patients with endometrioid adenocarcinoma of the uterine corpus. Our study was based on data from 206 patients who underwent complete surgical staging, including systematic pelvic and para‐aortic lymph node dissection. Two models resulted: one included depth of myometrial invasion, para‐aortic node metastasis and the number of sites involved by the tumor among the cervix, ovary and pelvic lymph nodes (which we designated as extracorporeal spread score, ECS) and the other incorporated nuclear grade and lymph‐vascular space invasion as variables. These 2 models enabled the prognosis for patients with endometrioid adenocarcinoma to be stratified into several levels according to hazard ratio. Comprehensive integration of the histopathologic prognostic factors, categorized into those relating to tumor extent and those relating to tumor virulence, should facilitate the estimation of individual prognosis more accurately than FIGO staging alone. Int. J. Cancer (Pred. Oncol.) 79:521–525, 1998.© 1998 Wiley‐Liss, Inc.

Cytogenetic analysis of uterine leiomyoma: the size, histopathology and GnRHa-response in relation to chromosome karyotype

OBJECTIVE The aim of this study was to elucidate the clinical characteristics of uterine leiomyomas having abnormal chromosome karyotype. STUDY DESIGN A total of 394 myomas were obtained from 213 patients for cytogenetic analysis. The size (number of nodules=144), histopathology (n=302), and gonadotropin-releasing hormone analogue (GnRHa)-response (n=58) were investigated in relation to chromosome karyotype in myomas. RESULTS 302 myomas from 166 patients were successfully karyotyped. A total of 21 myomas from 21 patients showed abnormal chromosome karyotype. The high frequencies of involved chromosomes 12, 14, 1, 7 were observed. The diameters of myomas with abnormal karyotype were significantly larger than those of myomas with normal karyotype. The frequency of the degeneration in myomas with abnormal karyotype was significantly higher than that with normal karyotype. The reduction rate in size of myomas by GnRHa treatments did not differ between the two types (karyotype normal versus abnormal) of nodules. CONCLUSIONS Chromosomally abnormal myomas were larger in diameter and showed a higher frequency of degeneration, suggesting that the cytogenetic background in uterine leiomyoma affects a tumors growth potential.

A prospective study on the efficacy of octreotide in the management of malignant bowel obstruction in gynecologic cancer.

Objective Malignant bowel obstruction (MBO), of which symptoms lead to a poor quality of life, is a common and distressing clinical complication in advanced gynecologic cancer. The aim of this study was to prospectively assess the clinical efficacy of octreotide to control vomiting in patients with advanced gynecologic cancer with inoperable gastrointestinal obstruction. Methods Patients with advanced gynecologic cancer, who presented at least one episode of vomiting per day due to MBO, were enrolled in this prospective study from 2006 to 2009. Octreotide was administered when necessary at doses starting with 300 &mgr;g up to 600 &mgr;g a day by continuous infusion for 2 weeks. Primary end point was vomiting control, which was evaluated by common terminology criteria for adverse events version 3 (CTCAE v3.0). Adverse events were also evaluated by CTCAE v3.0. Results Twenty-two cases were enrolled in this study. Octreotide controlled vomiting in 15 cases (68.2%) to grade 0 and 3 cases (13.6%) to grade 1 on CTCAE v3.0. Overall response rate to octreotide treatment was 81.8% in our patients’ cohort. Among 14 cases without nasogastric tube, the overall response rate was 93.1% (13/14). Among 8 cases with nasogastric tube, 4 cases were free of tube with decrease of drainage, and overall response rate was 62.5% (5/8). No major adverse events related to octreotide were reported. Conclusions We conclude that 300-&mgr;g/d dose of octreotide was effective and safe for Japanese patients with MBO by advanced gynecologic cancer. Octreotide could contribute to better quality of life by avoiding placement of nasogastric tube.

Tumor volume successively reflects the state of disease progression in endometrial cancer.

OBJECTIVE This study aimed to clarify the clinical significance of tumor volume in endometrial cancer. METHODS A total of 667 patients with endometrial cancer who underwent preoperative MRI and surgical treatment including lymphadenectomy were enrolled. As the surrogate marker of actual tumor volume, the volume index was defined as the product of the maximum longitudinal diameter along the uterine axis, the maximum intersecting anteroposterior diameter of the sagittal section image, and the maximum horizontal diameter of the horizontal section image from the MRI data. The volume index was divided into five categories: Group 1 (<8), Group 2 (8 to <27), Group 3 (27 to <64), Group 4 (64 to <125), and Group 5 (125 or more). The relationships between various clinicopathologic factors and volume index were investigated, and Cox regression analysis was conducted to assess the significance of volume index with respect to prognosis. RESULTS High-risk clinicopathologic findings increased with tumor volume. The lymph node metastasis rate was 3% in Group 1, 9% in Group 2, 17% in Group 3, 25% in Group 4, and 53% in Group 5. Cox regression analysis showed that the volume index (≥36) was a prognostic factor (hazard ratio: 2.0, 95% confidence interval: 1.3-3.1) independent of older age (≥58 years), high-risk histological grade/subtype, deep myoinvasion, lymph node metastasis, and type of surgery. CONCLUSION Tumor volume successively reflects the state of disease progression in endometrial cancer. The volume index can give information on both the staged prognosis and surgical management.

Long-term survival of patients with recurrent endometrial stromal sarcoma: a multicenter, observational study

Objective The aim of this study was to evaluate the clinical behavior and management outcome of recurrent endometrial stromal sarcoma (ESS). Methods A retrospective review of charts of 10 patients with recurrent ESS was performed and relapse-free interval, relapse site, treatment, response to treatment, duration of follow-up and clinical outcome extracted. Survival outcome measures used were post-relapse survival which was defined as the time from first evidence of relapse to death from any cause. Living patients were censored at the date of last follow-up. Results The median age and median relapse-free interval at the time of initial relapse were 51.5 years and 66.5 months, respectively. The number of relapses ranged from one to five. Sixteen surgical procedures for recurrent disease included nine (56.0%) complete resections. There was no statistically significant difference between initial recurrent tumors and second/subsequent recurrent tumors in the rate of complete surgery (44.4% vs. 71.4%, respectively, p=0.36). Of the eleven evaluable occasions when hormonal therapy was used for recurrent disease, disease control was achieved in eight (72.7%). There was no difference between initial recurrent tumors and second/subsequent recurrent tumors in disease control rate by hormonal therapy (85.7% vs. 50.0%, respectively, p=0.49). The 10-year post-relapse survival rate was 90.0% and the overall median post-relapse survival 119 months (range, 7 to 216 months). Conclusion Post-relapse survival of patients with ESS can be expected to be >10 years when treated by repeated surgical resection and hormonal therapy or both.