Takayoshi Nogawa

High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway

Purpose: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. Experimental Design: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. Results: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10−20). We validated its predictive ability with five other data sets using multivariate analysis (Tothills data set, P = 1 × 10−5; Bonomes data set, P = 0.0033; Dressmans data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response–related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. Conclusions: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. Clin Cancer Res; 18(5); 1374–85. ©2012 AACR.

Long-term survival in patients with para-aortic lymph node metastasis with systematic retroperitoneal lymphadenectomy followed by adjuvant chemotherapy in endometrial carcinoma.

Objective: The purposes of this study were to assess modified radical hysterectomy including systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy in patients with para-aortic lymph node (PAN) metastasis in endometrial carcinoma and to identify the multivariate independent prognostic factors for long-term survival during the past 10 years. Methods: Between December 1987 and December 2002, we performed modified radical hysterectomy with bilateral salpingo-oophorectomy including systematic pelvic and para-aortic lymphadenectomy and peritoneal cytology in 284 endometrial carcinoma patients according to the classification of the International Federation of Gynecology and Obstetrics (stage IA, n = 66; stage IB, n = 96; stage IC, n = 33; stage IIA, n = 5; stage IIB, n = 20; stage IIIA, n = 28; stage IIIC, n = 28; and stage IV, n = 8) who gave informed consents at our institute. Patients with tumor confined to the uterus (stages IC and II) were treated by 3 courses of cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, and cisplatin 75 mg/m2 regimen 3 to 4 weeks apart, and patients with extrauterine lesions involving adnexa and/or pelvic lymph node (PLN) were treated by 5 courses. In addition, 10 courses were given to patients with PAN metastasis. Patients with PLN metastasis received adjuvant chemotherapy, and adjuvant radiation was not part of our institutional protocol. For multivariate regression modeling with proportional hazards, the regression model of Cox was used. Survival curves were analyzed by the Kaplan-Meier method, and analysis of the differences was performed by the log-rank test. Results: The overall incidence of retroperitoneal lymph node metastasis assessed by systematic pelvic and para-aortic lymphadenectomy was 12.0% (34/284) in stages I to IV endometrial carcinoma, and incidences of PLN and PAN metastases were 9.2% (26/284) and 7.4% (21/284), respectively. However, PAN metastasis rate is 50% (13/26) in patients with PLN metastasis. Univariate analysis of prognostic factors revealed that International Federation of Gynecology and Obstetrics clinical stage (P < 0.0001), histological finding (P = 0.0292), myometrial invasion (P < 0.0001), adnexal metastasis (P < 0.0001), lymphovascular space invasion (P < 0.0001), tumor diameter (P = 0.0108), peritoneal cytology (P = 0.0001), and retroperitoneal lymph node metastasis (P < 0.0001) were significantly associated with 10-year overall survival. Survival was not associated with age (P = 0.1558) or cervical involvement (P = 0.1828). A multivariate analysis showed that adnexal metastasis (P = 0.0418) and lymphovascular space invasion (P = 0.0214) were significantly associated with 10-year overall survival. The 5- and 10-year overall survival rates in patients with negative PAN were 96% and 93% versus 72% and 62% in patients with positive PAN (P = 0.006). Conclusions: It is suggested that surgery with systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy could improve long-term survival in patients with PAN metastasis, although there are only 21 patients with PAN metastasis.

Maximum standardized uptake value of fluorodeoxyglucose positron emission tomography/computed tomography is a prognostic factor in ovarian clear cell adenocarcinoma.

Background Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is useful for diagnosing malignant tumors. Intracellular FDG uptake is measured as the standardized uptake value (SUV), which differs depending on tumor characteristics. This study investigated differences in maximum SUV (SUVmax) according to histologic type in ovarian epithelial cancer and the relationship of SUVmax with prognosis. Methods This study included 80 patients with ovarian epithelial cancer based on histopathologic findings at surgery and who had undergone PET/CT before treatment. Maximum SUV on PET/CT of primary lesions and histopathology were compared based on histologic type, and the prognosis associated with different SUVmax was evaluated. Results Clinical tumor stage was I in 35 patients, II in 8, III in 25, and IV in 12. Histologic type was serous adenocarcinoma (AC) in 33 patients, clear cell AC in 27, endometrioid AC in 15, and mucinous AC in 5. Median SUVmax was lower in mucinous AC (2.76) and clear cell AC (4.9) than in serous AC (11.4) or endometrioid AC (11.4). Overall, median SUVmax was lower in clinical stage I (5.37) than in clinical stage ≥II (10.3). However, in both clear cell AC and endometrioid AC, when histologic evaluation was possible, no difference was seen between stage I and stage ≥II. Moreover, in clear cell AC, the 5-year survival rate was significantly higher in the low-SUVmax group (100%) than in the high-SUVmax group (43.0%, P = 0.009). Conclusions Maximum SUV on preoperative FDG-PET/CT in ovarian epithelial cancer differs according to histologic type. In clear cell AC, SUVmax may represent a prognostic factor.

Potential impact of combined high‐ and low‐risk human papillomavirus infection on the progression of cervical intraepithelial neoplasia 2

Few studies have examined the effect of combined low‐risk human papillomavirus (LR‐HPV) and high‐risk human papillomavirus (HR‐HPV) infection on the progression of cervical intraepithelial neoplasia (CIN)2 to CIN3. This multi‐institutional prospective cohort study investigated the risk of progression of CIN2 with various combinations of HR‐HPV and LR‐HPV infection.

Clinicopathological prognostic factors and the role of cytoreduction in surgical stage IVb endometrial cancer: A retrospective multi-institutional analysis of 248 patients in Japan

OBJECTIVE To evaluate clinicopathological prognostic factors and the impact of cytoreduction in patients with surgical stage IVb endometrial cancer (EMCA). METHODS The records of 248 patients with stage IVb EMCA who underwent primary surgery including hysterectomy at multiple institutions from 1996 to 2005 were retrospectively analyzed. Data regarding disease distribution, surgical procedures, adjuvant therapy, and survival times were collected. Univariate and multivariate analyses were performed to identify factors associated with overall survival (OS). RESULTS The median OS was 24 months. The most common histological types were endometrioid (grade 1: 15%, grade 2: 20%, grade 3: 24%) and serous (17%). The most common sites of intra-abdominal metastases were pelvis (65%), ovaries (58%), omentum (58%), retroperitoneal lymph nodes (52%), and upper abdominal peritoneum (44%). In 93 patients with extra-abdominal metastases, the most common site was the lung (n=49). Complete resection of extra-abdominal metastases was achieved in only 13 patients. Complete resection of intra-abdominal metastases was achieved in 101 patients, 52 had ≤1 cm residual disease, and 95 had >1cm residual disease; the median OS times in these groups were 48, 23, and 14 months, respectively (p<0.0001). Multivariate analysis showed that performance status, histology/grade, adjuvant treatment, and intra-abdominal residual disease were independent prognostic factors. Intra-abdominal residual disease was an independent prognostic factor in patients with and without extra-abdominal metastases. CONCLUSIONS Cytoreductive surgery and adjuvant therapy may improve survival in stage IVb EMCA, particularly in patients with favorable prognostic factors, even in the presence of extra-abdominal metastases.

Vaginal hemangiopericytoma: a light microscopic and ultrastructural study

A case of a vaginal hemangiopericytoma in a 20-year-old woman was studied by light and electron microscopy. The neoplastic cells had round-to-oval nuclei with one or two nucleoli; fine chromatin; a foamy, cyanophilic cytoplasm; and an increased nuclear cytoplasmic ratio. Light microscopically, the tumor was composed of spindle-shaped or round cells proliferating around vascular spaces. Mitotic figures, necrosis, and hemorrhage were difficult to find. Electron microscopically, the neoplastic cells occurred in clusters, each of which was enclosed by a basal lamina. The cytoplasm contained abundant free ribosomes, flattened elements of rough endoplasmic reticulum, small Golgi apparatus, round or elongated mitochondria, lysosomes, glycogen particles, and sometimes pinocytotic vesicles and bundles of microfilaments with large dense spots. Desmosomes were also seen. In addition, the cytoplasmic process of the benign vascular pericytes was directly in contact with the neoplastic cells which had varying degrees of cytodifferentiation. The neoplastic cells in this lesion are consistent with an origin from pericytes, confirming the findings of this neoplasm when it arose in other sites.

Prospective evaluation of the Amplicor HPV test for predicting progression of cervical intraepithelial neoplasia 2

The aim of this study was to evaluate the clinical performance of the Amplicor HPV test, which detects 13 high‐risk human papillomaviruses (HR‐HPV), and to determine the association between consistent HR‐HPV infection and progression of cervical intraepithelial neoplasia (CIN) 2 to CIN3.

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.

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.

The Role of Modified Radical Hysterectomy in Endometrial Carcinoma

Improvement of the treatment results in patients with endometrial carcinoma has been achieved by a multidisciplinary approach including surgery, chemotherapy and radiotherapy, similar to the case for many other carcinomas. Although total hysterectomy/bilateral salpingo-oophorectomy (TH/BSO), pelvic and para-aortic lymphadenectomy and peritoneal cytology are often required, cases with early carcinomas predominate among cases of endometrial carcinoma, and TH/BSO alone is sufficient to achieve a favorable prognosis in such cases. The recommended surgical procedure for the staging of a patient with endometrial carcinoma clinically confined to the fundal portion of the uterus includes peritoneal cytology and TH/BSO with pelvic and para-aortic lymphadenectomy (National Comprehensive Cancer Network, 2011). For operable patients with cervical involvement, peritoneal cytology and radical hysterectomy/bilateral salpingooophorectomy with pelvic and para-aortic lymphadenectomy should be considered. However, radical hysterectomy always has a major adverse effect with dysuria. Improvement of the treatment results and quality of life (QOL) can also be expected from modified radical hysterectomy performed in appropriately selected patients. One of the advantages of modified radical hysterectomy is that it can be switched from radical hysterectomy in high-risk patients in terms of the age, obesity and presence of medical complications. For operable patients with intra-abdominal disease, surgical procedure includes peritoneal cytology, TH/BSO with pelvic and para-aortic lymphadenectomy, and maximal debulking. The pathologic information obtained also provides an optimal basis for the selection of adjuvant therapy. Therefore, complete surgical staging including pathologic and prognostic data on which to base decisions regarding adjuvant therapy should be required for all patients who do not have medical or technical contraindication to lymphadenectomy.