[Metastatic mechanisms of uterine malignancies and therapeutic consequences]. / Metastasierung von Malignomen des Uterus und therapeutische Konsequenzen.

Malignancies of the uterus metastasize by direct invasion of neighboring structures, lymphatically or hematogenously. Endometrial and cervical cancers lymphatically spread to the pelvic and para-aortic lymph nodes. For endometrial cancer the depth of myometrial invasion, lymphosvascular space involvement (LVSI) and a microcystic, elongated and fragmented (MELF) glandular invasion pattern are predictors for lymph node metastases. Metastases to the pelvic lymph nodes occur in approximately 10 % of endometrial cancer patients and in 30 % of these cases the para-aortic lymph nodes are also involved. Sentinel lymph node biopsy is possible for clinical stage I endometrial cancer and early stages of cervical cancer but is not yet routine. The presence of LVSI is considered to be the strongest predictor of distant metastases, particularly if assessed by immunohistochemistry with antibodies against factor VIII-related antigen or CD31. Endometrioid and clear cell carcinomas can hematogenously metastasize to the lungs, bones, liver and brain and can rarely be manifested as a solitary metastasis. In contrast, serous carcinomas can show extensive peritoneal spread. To date molecular biomarkers cannot predict the occurrence of distant metastasis. Overexpression of P53, p16 and L1CAM have been identified as negative prognostic factors and are associated with the prognostically unfavorable serous tumor type. The metastatic spread of squamous cell cervical cancer is strongly associated with tumor volume. Microinvasive carcinomas have a very low rate of parametrial and lymph node involvement and do not require radical hysterectomy. In contrast, lymph node metastases occur in up to 50 % of bulky stages IB and II cervical cancers. Distant metastases can occur in the lungs, liver, bones and brain. Molecular biomarkers have not been shown to predict metastatic spread. In well-differentiated adenocarcinoma of the cervix the pattern of invasion is strongly predictive for the presence of lymph node metastases, irrespective of tumor size and depth of invasion.

Morcellation of occult uterine malignancies: an Australian single institution retrospective study.

INTRODUCTION: Morcellation for tissue extraction during laparoscopic hysterectomy or myomectomy has recently been questioned because of the potential to spread occult uterine cancers. The Australian Therapeutic Goods Administration (TGA) issued a safety advisory in August 2014, estimating the risk of occult malignancy in the Australian population to be one in 1000 or lower, based on estimates from overseas studies in the absence of any local data. AIMS: The aim of this study was to determine the incidence of occult uterine malignancies in morcellated surgical specimens at St John of God Hospital in Perth, Western Australia. MATERIALS AND METHODS: All women who had a hysterectomy or myomectomy with morcellation of the surgical specimen for presumed benign uterine fibroids at our institution from 01 November 2009 to 12 March 2015 were identified and stratified into benign disease, uncertain malignant potential and malignant. RESULTS: Seven hundred and thirty-four women were included, and three malignancies were identified: two cases with leiomyosarcoma (LMS) and another with an endometrioid endometrial adenocarcinoma (EAC). One case of serous tubal in situ carcinoma (STIC) and two cases of benign metastasising leiomyoma/leiomyomatosis were also identified. The overall risk of malignancy in a morcellated surgical specimen was 0.41% (three in 734). The risk of morcellating an incidental uterine malignancy was 0.27% for LMS and 0.14% for EAC. All three incidental malignancies were diagnosed in premenopausal women. CONCLUSIONS: The risk of unintended morcellation of uterine malignancy in our study is higher than that estimated by the Australian TGA and highlights the urgent need for further studies in Australia.

Synthetic cyanoacrylic glue in the prevention of post-operative lymphocele after pelvic lymphadenectomy in patients with uterine malignancies: A prospective, single-blind, preliminary study.

OBJECTIVES: Lymphoceles are among the most common post-operative complications of pelvic lymphadenectomy, with a reported incidence of 1% to 29% in gynecology oncology. Several studies evaluated the effectiveness of biological glues on reducing lymphoceles, but no data on gynecological patients are available. We evaluated the effectiveness of cyanoacrylic glues (n-butyl cyanoacrylate) (Glubran 2 - GEM s.r.l., Italy) in preventing lymphocele on 30 patients who underwent pelvic lymphadenectomy for endometrial or cervical cancer. METHODS: Single-blind prospective randomized study. Patients were divided into 2 groups: pelvic lymphadenectomy plus n-butyl cyanoacrylate (treatment group: 44 patients) and pelvic lymphadenectomy without n-butyl cyanoacrylate (control group: 44 patients). Primary endpoint was incidence of pelvic lymphocele in the two groups 30 days after surgery, and evaluated with pelvic ultrasound and RMI examination. Secondary endpoints evaluated drainage volume of lymphorrhea 36, 48, 72 and 96 h after surgery. RESULTS: 15% in the treatment group and 36.6% in the control group had lymphocele 1month after the procedure (p<0.03; RR 0.4 [95% CI 0.152-0.999]). Concerning the secondary outcome in group A the amount of lymphorrhea presented a constant significant decrease during evaluation; on the contrary, in group B, after an initial decrease at 48 h, the amount of lymphorrhea remained unchanged; at all considered times the amount of lymphorrhea resulted significantly greater in controls. CONCLUSION: Intraoperative application of n-butyl cyanoacrylate seems to reduce lymph production after pelvic lymphadenectomy, providing a useful additional treatment option for reducing drainage volume and preventing lymphocele development after pelvic lymphadenectomy.

Potential bioactive compound and hub gene identification of endometrial carcinoma using systems biology.

Endometrial carcinoma is a frequent cancer of the female genital tract. Endometrial carcinoma accounts for 97% of all uterine malignancies and 3 % of sarcomas that develop from the endometrium's glands. Endometrial cancer is frequently found in its early stages since most women quickly report postmenopausal vaginal hemorrhage. The need for more advanced medications to improve survival in such situations is still unfulfilled. As a result, there is growing interest in employing an herbal treatment to treat endometriosis, which seems to be an effective strategy. We have discovered a few unintended targets (ligands) in our investigation that are active components of common therapeutic herbs. The differentially expressed genes (DEG - target protein) for endometrial cancer were found using the NCBI and CIViC databases. In our investigation, the protein used for docking and simulation was PDB ID: 3THW. Using the Cytoscape server, the gene-encoding protein network has been identified. It was discovered that the Protein 3THW's binding energy to the bioactive substance (Asarone) was -7.15 Kcal/mol. It was discovered that the crucial interacting amino acid residues were ILE648, PHE650, ILE651, VAL802, TYR815, VAL817. The properties of the pharmaceutical target are further investigated by employing a molecular simulation study for 100 ns with NAMD software. Low RMSD and SASA (Solvent accessible surface area), high RMSF, High hydrogen bonds, between Asarone and MSH2 demonstrated their potency as endometrial cancer inhibitor compounds. Based on these analyses we infer that the bioactive substances originating from medicinal plants may be an effective treatment for endometrial cancer.Communicated by Ramaswamy H. Sarma.

Germline multigene panel testing of patients with endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

SMARCA4-deficient uterine sarcoma: A case report and a concise review.

BACKGROUND: SMARCA4-deficient uterine sarcoma (SDUS) is a newly discovered undifferentiated uterine mesenchymal malignancy which has loss of expression of SMARCA4. CASE: A 46-year-old woman presented with heavy irregular vaginal bleeding over the previous 5 months. Computed tomography and magnetic resonance imaging showed a large pelvic mass centered within the uterus, suspicious of malignancy with regional metastatic lymphadenopathy. Biopsy confirmed SDUS and patient underwent chemotherapy. Her symptoms improved 3 months after treatment. CONCLUSION: An extremely rare case of this newly described entity is reported. Recognizing the characteristic imaging and pathology findings of SDUS is essential for an accurate diagnosis, which may affect patient survival.

Recurrent Uterine Smooth-Muscle Tumors of Uncertain Malignant Potential (STUMP): State of The Art.

The term 'uterine STUMP' (smooth-muscle tumors of uncertain malignant potential) is currently used to define a heterogeneous group of uterine tumors distinct from leiomyomas and leiomyosarcomas. This rare entity is often characterized by a slow growth and protracted patient survival when compared to leiomyosarcomas but few data are available about its clinical management and outcome. In this review, we summarize the current state of knowledge about uterine STUMP, with a particular focus on cases of recurrence.

Outcome and Predictive Factors in Uterine Carcinosarcoma Using Postoperative Radiotherapy: A Rare Cancer Network Study.

Uterine carcinosarcomas (UCS) are rare tumors. Consensus regarding therapeutic management in non-metastatic disease is lacking. This study reports on outcome and predictive factors when using postoperative radiotherapy. We analyzed a retrospective analysis in 124 women treated between 1987-2007 in the framework of the Rare-Cancer-Network. Median follow-up was 27 months. Postoperative pelvic EBRT was administered in 105 women (85%) and 92 patients (74%) received exclusive or additional vaginal brachytherapy. Five-year overall survival (OS), disease-free survival (DFS), cancer specific survival (CSS) and locoregional control (LRC) were 51.6% (95% CI 35-73%), 53.7% (39-71%), 58.6% (38-74%) and 48% (38-67%). Multivariate analysis showed that external beam radiation therapy (EBRT) >50Gy was an independent prognostic factor for better OS (P=0.03), CSS (P=0.02) and LRC (P=0.01). Relative risks (RR) for better OS (P=0.02), DFS (P=0.04) and LRC (P=0.01) were significantly associated with younger age (≤60 years). Higher brachytherapy (BT)-dose (>9Gy) improved DFS (P=0.04) and LRC (P=0.008). We concluded that UCS has high systemic failure rate. Local relapse was reduced by a relative risk factor of over three in all stages of diseases when using higher doses for EBRT and brachytherapy. Postoperative RT was most effective in UCS stage I/II-diseases.