Kiyoshi Fujiwara

Parametrial involvement in FIGO stage IB1 cervical carcinoma diagnostic impact of tumor diameter in preoperative magnetic resonance imaging.

Background: In the surgical treatment for early-stage cervical carcinoma, it is important to identify preoperatively a low-risk group of patients as candidates for less radical surgery to avoid the morbidity associated with radical hysterectomy. The aim of this study was to evaluate the correlation between tumor diameter measured preoperatively using magnetic resonance imaging (MRI) and pathological prognostic factors in International Federation of Gynecology and Obstetrics (FIGO) stage IB1 cervical carcinoma. Methods: A total of 125 patients with FIGO stage IB1 cervical cancer were included in this study. Clinical records, pathology reports, and MRI findings were retrospectively reviewed. Results: Histological diagnosis was squamous cell carcinoma in 57 patients and nonsquamous cell carcinoma in 68 patients. All patients underwent preoperative evaluation by MRI within a median period of 13.5 days before surgery. The tumor diameter measured by MRI ranged from zero (no tumor detected) to 42 mm, with a median of 23 mm. Pathological prognostic factors included parametrial involvement, lymph node metastasis, deep stromal invasion, and lymphovascular space invasion. All these factors were found less frequently in patients with a smaller tumor diameter. Most notably, parametrial involvement was seen in none of the patients with tumors 20 mm or less and was detected only in patients with tumors greater than 20 mm (P = 0.01). Conclusions: In the FIGO stage IB1 cervical carcinoma, the tumor diameter measured preoperatively by MRI correlates well with other pathological prognostic factors, especially with parametrial involvement. This finding suggests that the tumor diameter measured in preoperative MRI may serve as a strong predictor of parametrial involvement in FIGO stage IB1 cervical carcinoma, which can be used to select a candidate population for less radical surgery without the need for a cone biopsy before hysterectomy.

Histopathology predicts clinical outcome in advanced epithelial ovarian cancer patients treated with neoadjuvant chemotherapy and debulking surgery

OBJECTIVE To analyze the factors prognostic of survival in patients with advanced epithelial ovarian cancer (EOC) treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery. METHODS Outcomes were retrospectively in patients with advanced EOC or peritoneal cancer who received neoadjuvant paclitaxel and carboplatin chemotherapy every 3 weeks for three to four cycles, followed by interval debulking surgery and three additional cycles of the same regimens from January 2001 to November 2010. Therapeutic response was assessed histopathologically as grade 0 to 3, based on the degree of disappearance of cancer cells, displacement by necrotic and fibrotic tissue, and tumor-induced inflammation. Factors prognostic of progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS The 124 enrolled patients had a median age of 62 years (range, 35-79 years). Viable cancer cells were observed in specimens resected from 72 patients (58%) at interval debulking surgery after NAC. Multivariate analysis using the Cox proportional hazard model showed that advanced (stage IV) disease (hazard ratio [HR]=1.94, p=0.003), residual cancer at the end of surgery ≥1cm (HR=3.78, p<0.001), and histological grade 0-1 (HR=1.65, p=0.03) were independent predictors of decreased OS. Grade 0-1 was also an independent predictor of increased risk of relapse within 6 months (odds ratio=8.42, p=0.003). CONCLUSIONS Residual disease of ≥1cm, advanced stage, and the presence of more viable disease in resected specimens are prognostic factors for survival in advanced EOC patients receiving NAC followed by interval debulking surgery.

Type II versus type III fertility-sparing abdominal radical trachelectomy for early-stage cervical cancer: a comparison of feasibility of surgical outcomes.

Objective The purpose of this study was to compare surgical outcomes using modified (type II) and traditional (type III) abdominal radical trachelectomy (ART) for fertility-sparing surgery in early cervical cancer. Methods A prospectively maintained database of ART procedures was analyzed. Data were collected regarding age, stage, histology, operative outcome, surgical complication, and fertility outcome. Results We performed 23 fertility-sparing ARTs for patients with International Federation of Gynecology and Obstetrics stages IA to IB1 tumors of less than 2 cm between 2006 and 2010. Type III ART was attempted in 8 patients and modified ART in 15 patients. The median operating time was greater in the type III group compared with that in the type II group (305 vs 247 minutes; P < 0.02). The median surgical blood loss was greater in the type III ART group (580 mL; range, 250–988 mL) compared with that in the modified type II group (366 mL; range, 200–850 mL; P < 0.05). The median time to recovery of bladder dysfunction was less in the type II group (9 days; range, 3–10 days) than that in the type III group (13 days; range, 10–23 days; P < 0.01). There were no recurrences at the time of this report. Conclusions Type II ART provides surgical and pathological outcomes with better recovery of bladder function similar to those in type III ART. For patients with early cervical cancer who wish to preserve reproductive function, type II ART is a feasible and safe operation.

Clinical tumor diameter and prognosis of patients with FIGO stage IB1 cervical cancer (JCOG0806-A)

OBJECTIVE In order to determine indications for less radical surgery such as modified radical hysterectomy, the risk of pathological parametrial involvement and prognosis of FIGO stage IB1 cervical cancer patients undergoing standard radical hysterectomy with pre-operatively assessed tumor diameter≤2 cm were investigated. METHODS We conducted a retrospective multi-institutional chart review of patients with FIGO stage IB1 cervical cancer who underwent primary surgical treatment between 1998 and 2002. The eligibility criteria for the analyses were (i) histologically-proven squamous cell carcinoma, adenocarcinoma or, adenosquamous cell carcinoma, (ii) radical hysterectomy performed, (iii) clinical tumor diameter data available by MR imaging or specimens by cone biopsy, and (iv) age between 20 and 70. Based on the clinical tumor diameter, patients were stratified into those with the following tumors: i) 2 cm or less (cT≤2 cm) and ii) greater than 2 cm (cT>2 cm). We expected 5-year OS of ≥95% and parametrial involvement<2-3% for patients with cT≤2 cm who underwent radical hysterectomy. RESULTS Of the 1269 patients enrolled, 604 were eligible for the planned analyses. Among these, 571 underwent radical hysterectomy (323 with cT≤2 cm and 248 with cT>2 cm). Parametrial involvement was present in 1.9% (6/323) with cT≤2 cm and 12.9% (32/248) with cT>2 cm. Five-year overall survivals were 95.8% (95% CI 92.9-97.6%) in cT≤2 cm and 91.9% (95% CI 87.6-94.8%) in cT>2 cm patients. CONCLUSION Patients with cT≤2 cm had lower risk of parametrial involvement and more favorable 5-year overall survival. They could therefore be good candidates for receiving less radical surgery.

VAV1 represses E-cadherin expression through the transactivation of Snail and Slug: a potential mechanism for aberrant epithelial to mesenchymal transition in human epithelial ovarian cancer

Ovarian cancer is the most lethal gynecological malignancy in the western world. Although patients with early-stage ovarian cancer generally have a good prognosis, approximately 20%-30% of patients will die of the disease, and 5-year recurrence rates are 25%-45%, highlighting the need for improved detection and treatment. We investigated the role of VAV1, a protein with guanine nucleotide exchange factor activity, which is associated with survival in patients with early-stage ovarian cancer (International of Obstetrics and Gynecology [FIGO] stages I and II). We analyzed 88 samples from patients with primary epithelial ovarian cancer, which were divided into FIGO stages I and II (n = 46), and III and IV (n = 42). Prognostic analysis revealed that upregulated VAV1 expression correlated significantly with poor prognosis in patients with early-stage epithelial ovarian cancer (P ≤ 0.05), but not with other clinicopathologic features. Stable overexpression of VAV1 in human high-grade serous ovarian cancer SKOV3 cells induced morphologic changes indicative of loss of intercellular adhesions and organized actin stress fibers. Western blotting and real-time reverse transcriptase-polymerase chain reaction demonstrated that these cells had downregulated E-cadherin protein and messenger RNA levels, respectively. This downregulation is associated with epithelial-mesenchymal transition (EMT) and invasive cancer. Furthermore, VAV1 overexpression in both SKOV3 and human ovarian surface epithelial cells demonstrated that its upregulation of an E-cadherin transcriptional repressor, Snail and Slug, was not confined to ovarian cancer cells. Conversely, knockdown of VAV1 by RNA interference reduced Snail and Slug. Our findings suggest that VAV1 may play a role in the EMT of ovarian cancer, and may serve as a potential therapeutic target.

Absence of human papillomavirus infection and activation of PI3K-AKT pathway in cervical clear cell carcinoma.

Objective Cervical cancer is the second most common cancer in females worldwide, and the majority of squamous cell carcinomas and adenocarcinomas are associated with high-risk human papillomavirus (HPV) infection. However, the relationship between clear cell carcinoma of the cervix (CCCC) and HPV is unclear. In this study, we sought to determine if HPV infection is associated with CCCC and to elucidate the signaling pathways involved. Methods We collected samples from 13 CCCC patients and collated the relevant clinicopathologic data. We then evaluated the presence of HPV types 16, 18, 31, 33, 35, 52, and 58 by broad-spectrum amplification by polymerase chain reaction and HPV types 39, 45, 51, 56, 59, and 68 by nested polymerase chain reaction assay that combines degenerate E6/E7 consensus primers and type-specific primers from extracted genomic DNA. Immunohistochemistry was used to analyze the expression of EGFR (epidermal growth factor receptor), HER2, PTEN (phosphatase and tensin homolog), phospho-AKT, phospho-mTOR (mammalian target of rapamycin), p16INK4a, and p53. EGFR and HER2 gene amplification was determined by fluorescence in situ hybridization. Results Patients with stage IB CCCC had a better 3-year overall survival rate compared with those with advanced-stage cancer (100% vs 44%; P = 0.014). High-risk HPVs were not detected in any of the cases examined. EGFR immunostaining was observed in 9 (75%) of 12 patients, HER2 in 3 (25%) of 12, PTEN in 6 (50%) of 12, and phospho-AKT in 7 (58%) of 12, and phospho-mTOR in 6 (50%) of 12. EGFR amplification could not be detected, but HER2 amplification was identified in 1 of (12.5%) 8 cases. Conclusions Patients with stage I CCCC demonstrated good overall survival and rare recurrence. Clear cell carcinoma of the cervix is unrelated to high-risk HPV infection; hence, current vaccines will not prevent the incidence of CCCC. However, increased EGFR or HER2 expression or activation of AKT or mTOR was observed in all cases, indicating that inhibitors of tyrosine kinases or the AKT-mTOR pathway may be suitable treatment regimens for CCCC.

Phase I study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel chemotherapy for locally advanced cervical carcinoma in Japanese women.

The purpose of this study was to evaluate the use of concurrent chemoradiotherapy involving weekly administration of cisplatin and paclitaxel for the treatment of locally advanced cervical carcinoma in Japanese women. Twenty Japanese patients were registered for this phase I study. Radiation therapy was performed using external irradiation and high-dose rate intracavitary irradiation of the pelvis. Chemotherapy was performed once a week until termination of the radiation therapy. The dose of cisplatin was decided as 30 mg/m2, and the initial dose of paclitaxel was set as 30 mg/m2, with a planned incremental increase of 10 mg/m2 up to 70 mg/m2. When 3 to 6 patients were registered at each dose level and dose-limiting toxicity (DLT) was noted in more than 3 patients, the dose level was assumed to be the maximum tolerated dose. Among the 20 patients, 1 patient experienced DLT during 2 courses because of dehydration and arrhythmia. In another patient, chemotherapy was discontinued after 4 courses because of a hypersensitivity reaction to paclitaxel at dose level 3. No patient experienced DLT resulting from hematologic toxicities. All patients underwent radiation therapy according to schedule without any discontinuations. A complete response was obtained in 16 patients. Based on the results obtained from this study, weekly administration of 30 mg/m2 cisplatin and 50 mg/m2 paclitaxel with concurrent chemoradiotherapy can be considered a tolerable and safe dose for the treatment of locally advanced cervical carcinoma in Japanese women.

Clinical Features of Neuroendocrine Carcinoma of the Uterine Cervix: A Single-Institution Retrospective Review.

Objective Neuroendocrine carcinoma of the cervix is a rare and aggressive subtype of cervical cancer and includes small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). We conducted a single-institution retrospective review to explore the pattern of treatments and outcomes with the aim of defining an optimum treatment strategy for these carcinomas. Methods Twenty-three consecutive patients with SCNEC or LCNEC of the cervix diagnosed at the Hyogo Cancer Center between 1996 and 2013 were included in this study. Pertinent information, including clinical and pathological characteristics, and survival data were collected from clinical records and/or telephone surveys. The pathological review was conducted by a pathologist specializing in gynecologic cancer. Results Eleven patients had SCNEC and 12 had LCNEC. Eighteen patients with International Federation of Gynecology and Obstetrics (FIGO) stage I/II underwent type III radical hysterectomy with pelvic lymphadenectomy. After surgery, 9 received adjuvant chemotherapy (8, irinotecan plus cisplatin; 1, paclitaxel plus carboplatin), 7 received concurrent chemoradiation therapy (CCRT; 6, nedaplatin; 1, cisplatin), and 2 received radiation therapy (RT). Patients who received adjuvant chemotherapy had a better overall survival than did patients who received CCRT or RT (hazard ratio, 0.21; 95% confidence interval, 0.030–1.51; P = 0.12). Although the overall survival rates are not statistically significant, the 9 patients who underwent radical hysterectomy followed by adjuvant chemotherapy are all alive. Among the remaining 5 patients who did not undergo radical hysterectomy, 2 with FIGO stage III and 1 with stage IVa received CCRT, and 2 with stage IVb received palliative RT or chemotherapy. These 5 patients with FIGO stage III/IV died of disease within 36 months. Conclusions Radical hysterectomy followed by platinum-based chemotherapy, especially the irinotecan plus cisplatin combination, is beneficial for long-term survival in patients with early-stage neuroendocrine carcinoma of the cervix.

Cytologic features of gastric-type adenocarcinoma of the uterine cervix

Gastric‐type mucinous carcinoma (GAS) is a clinically aggressive variant of cervical adenocarcinoma. This study sought to describe the cytologic features of GAS.

Alpha-fetoprotein-producing ovarian clear cell adenocarcinoma simulating fetal gut in a postmenopausal woman.

•A 59-year-old postmenopausal woman had ovarian clear cell adenocarcinoma producing AFP.•The tumor lacked a yolk sac component and formed ducts similar to the fetal gut.