Akira Mitsuhashi

Impact of immunohistochemistry-based molecular classification with conventional risk stratification on recurrence and survival outcomes in endometrial cancer

The conventional histomorphology-based risk classification for endometrial cancer (EC) does not consider the molecular heterogeneity that influences prognosis and treatment response. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) system uses next-generation sequencing to assess DNA polymerase epsilon (POLE) mutations, but its high cost limits its accessibility. This study evaluated the prognostic value of a novel algorithm that combined immunohistochemistry (IHC) testing with conventional risk factors. This retrospective study included 237 patients with stage I-III EC who underwent surgery. Low-risk patients were classified without IHC, while intermediate- and high-risk patients were categorized as MMR-deficient (MMRd), p53-abnormal (p53abn), or nonspecific molecular profile (NSMP) groups based on IHC. Additionally, L1CAM expression was also evaluated. Survival outcomes were analyzed using Kaplan-Meier curves and Cox regression models. Data from 233 cases were analyzed; the median follow-up duration was 63 months. Among 87 low-risk patients, only 1 experienced recurrence. The intermediate- and high-risk groups were subdivided into 42 MMRd, 16 p53abn, and 88 NSMP patients. The 5-year disease-free survival (DFS) rates were 98.8% (low-risk), 94.7% (NSMP), 80.6% (MMRd), and 59.8% (p53abn), highlighting the poorer prognosis of p53abn. p53abn independently predicted recurrence (hazard ratio [HR], 10.1) and mortality (HR, 25.6). L1CAM positivity correlated with worse DFS but was not an independent prognostic factor. Conventional risk classification combined with IHC classification using p53 and MMR is a cost-effective prognostic tool that enables risk stratification and personalized treatment decisions, even when genetic testing is unavailable.

Evaluation of the usefulness of sentinel lymph node mapping using indocyanine green in patients with cervical and endometrial cancers: A single‐center prospective exploratory study

AbstractAimSentinel lymph node (SLN) mapping using indocyanine green (ICG) is an alternative for reducing comprehensive lymph node dissection and its associated morbidity. This trial aimed to assess the efficacy and safety of ICG for SLN detection in patients with cervical and endometrial cancers at a single academic teaching hospital.MethodsThis single‐arm, open‐label trial conducted at Chiba University Hospital included patients with endometrial or cervical cancer, aged 20–70 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1. ICG was injected into the uterine cervix after anesthesia induction. For patients with endometrial cancer, ICG was additionally injected into the uterine myometrium after laparotomy. Imaging‐assisted surgery was then performed to locate and remove the SLNs. Systematic pelvic lymph node dissection was performed as the standard procedure, with additional para‐aortic lymph node dissection in selected cases.ResultsThe overall and bilateral SLN detection rates were 80.4% (37/46) and 50.0% (23/46), respectively. SLN identification was successful in 37 patients. Of these, 34 had pathologically negative SLNs, and all of them showed no lymph node metastasis in the backup dissection (negative predictive value: 100%). The remaining three cases had pathologically positive SLNs. No adverse events were observed in a total of 49 enrolled patients.ConclusionsICG injection was found to be safe. SLN mapping using ICG has demonstrated significant potential in reducing surgical interventions and associated complications in the treatment of early‐stage gynecological cancers.

High prevalence of pulmonary embolism prior to cancer therapies in patients with ovarian and endometrial cancers detected by contrast‐enhanced CT using D‐dimer as an index

AbstractObjectiveWe aimed to evaluate the prevalence of pulmonary embolism (PE) before cancer therapies in patients with ovarian and endometrial cancers with enhanced computed tomography (CT) using D‐dimer (DD), and determine the optimal cut‐off level of DD.MethodsSince 2009, we have performed preoperative venous thromboembolism (VTE) screening of patients with ovarian and endometrial cancer. For patients with DD levels of more than 1.0 μg/ml, enhanced CT images were obtained from the pulmonary apex to the foot to detect PE and deep venous thrombosis (DVT) simultaneously.ResultsAmong patients with ovarian cancer, 84 of 413 (20.3%) had VTEs (DVT alone, n = 31 [7.5%]; PE with or without DVT, n = 53 [12.8%]; PE alone, n = 12 [2.9%]). Among patients with endometrial cancer, 50 of 455 (11.0%) had VTEs (DVT alone, n = 19 [4.2%]; PE with or without DVT, n = 31 [6.8%], PE alone, n = 14 [3.1%]). The optimal cut‐off level of DD was estimated to be ≥1.5 and ≥1.2 μg/ml in ovarian and endometrial cancers, respectively.ConclusionOur study revealed a high prevalence of PE before cancer therapies in patients with ovarian and endometrial cancers by enhanced CT using DD.

Medroxyprogesterone acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and endometrial carcinoma: trial protocol for a prospective, randomised, open, blinded-endpoint design, dose-response trial (FELICIA trial)

Introduction Progestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission. Methods and analysis A randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years. Ethics and dissemination The protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal. Trial registration number Japan Registry of Clinical Trials (jRCT2031190065).

A Case Study of a High-Grade Serous Carcinoma of the Fallopian Tube Transformed into Carcinosarcoma at the Site of Peritoneal Dissemination With Immunohistological Evidence of an Epithelial–Mesenchymal Transition

We report a patient in whom a primary high-grade serous carcinoma (HGSC) of the fallopian tube transformed into a carcinosarcoma at the site of peritoneal dissemination, and immunohistological analysis suggested the involvement of an epithelial–mesenchymal transition (EMT). The patient, a 70-year-old woman, had an abdominal mass palpated on admission, and a laparotomy was performed after a close examination. The resected right fallopian tube was cystically dilated, and a solid mass was observed in its lumen. The histological diagnosis was HGSC of the right fallopian tube with a papillary or complex tubular structure composed of tumor cells with marked nuclear irregularities. p53 was overexpressed, and no mesenchymal tumor component was observed. The resected left-sided abdominal mass of the omentum was a solid with a long diameter of 100 mm. Microscopically, the tumor exhibited a mixture of HGSC and high-grade sarcoma with nonspecific differentiation. Furthermore, a heterologous chondrosarcoma was subsequently observed from the high-grade sarcoma. The HGSC component was E-cadherin positive. The high-grade sarcoma component was positive for EMT-related proteins such as zinc finger E-box–binding homeobox 1 (ZEB1) and twist family bHLH transcription factor 1 (TWIST1). The chondrosarcoma component was ZEB1 positive and TWIST1 negative. p53 overexpression was found in all 3 components. The tumor of the omentum suggested that an EMT phenomenon was involved in the tumorigenesis. In this scenario, the primary HGSC of the fallopian tube with obvious invasion demonstrated that the conversion from carcinoma to sarcoma by EMT occurs only with peritoneal dissemination.

Resolution of pelvic postoperative spindle cell nodule with sarcomatous onset after 9 years of follow‐up

AbstractIntroductionPostoperative spindle cell nodules are benign and reactive lesions that occur at the previous surgical site. It often develops like a sarcoma and is resected via highly invasive procedures. To date, there have been no published reports on the natural progression of postoperative spindle cell nodules without surgical intervention.CaseA 45‐year‐old woman underwent a total abdominal hysterectomy for leiomyoma. A 5‐cm pelvic mass exposed in the vaginal stump developed 7 weeks later, causing genital bleeding. Positron emission tomography–computed tomography revealed a pelvic mass and an enlarged pelvic lymph node with high uptake. We suspected an invasive sarcoma in the pelvis. However, through a transvaginal needle biopsy, the mass was diagnosed as a postoperative spindle cell nodule posthysterectomy. The nodule slowly reduced in size and completely disappeared 9 years posthysterectomy.ConclusionsCorrect diagnosis of this nodule with sarcomatous onset based on biopsy was important to avoid unnecessary surgeries. The lesion completely disappeared spontaneously after long‐term follow‐up.

Trends and characteristics of fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer in Japan: a survey by the Gynecologic Oncology Committee of the Japan Society of Obstetrics and Gynecology

The objective of this study was to examine the current trends in fertility-sparing (FS) treatment for young atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) patients in Japan. This study was conducted by the Committee on Gynecologic Oncology of the Japan Society of Obstetrics and Gynecology (JSOG) in the 2017-2018 fiscal year. A nationwide, retrospective questionnaire-style survey-as performed. We collected the data of 413 patients from 102 JSOG gynecological cancer registered institutions. FS treatment was performed with medroxyprogesterone (MPA) (87.2%) or MPA + metformin (11.6%). Pathological complete remission (CR) after initial treatment was achieved in 78.2% of patients. The significant clinicopathological factors correlated to CR after initial treatment were histology (AEH vs. endometrioid carcinoma grade 1 [ECG1]), body mass index (BMI) (<25 vs. ≥25 kg/m²), and treatment period (<6 vs. ≥6 months). ECG1, time to complete remission (TTCR) ≥6 months, maintenance therapy (-), and pregnancy (-) were associated with a significantly higher risk of recurrence on multivariate analysis. The total pregnancy rate was 47%, and the live birth rate was 40.1%. Patients who received infertility treatments showed a higher live birth rate (50.6%) than those who did not (7.7%). In this survey, we confirmed that FS treatment in Japan is centered on MPA alone and in combination with metformin, and that the treatment efficacy is similar to that reported in previous reports. A multicenter survey study in Japan showed FS treatment for young AEH and EC patients in compliance with the indications is feasible.