An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

Objectives

The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification.

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients

ObjectiveLynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.Methods341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13–12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.ResultsTwenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).ConclusionsSince double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.     

The detection of microsatellite instability in blind endometrial samples—a potential novel screening tool for endometrial cancer in women from hereditary nonpolyposis colorectal cancer families?

Microsatellite instability (MSI) is the phenotypic molecular characteristic of the majority of tumors associated with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC). Women in this group have an increased risk of endometrial cancer (EC). This study aimed to determine whether MSI could be demonstrated in blind endometrial samples from women with EC, HNPCC kindreds undergoing screening for EC, and women with normal endometrium. Twenty-four women with EC, 20 women from HNPCC kindreds, and 20 women undergoing gynecological surgery for benign indications underwent blind sampling. MSI analysis was performed by conventional polymerase chain reaction using fluorescent-labeled primers and automated analysis. Twelve microsatellites were studied with MSI defined as evident when novel alleles were seen in endometrial biopsy samples compared to genomic DNA. Of the 24 EC samples obtained, sufficient DNA for analysis was extracted in 17 cases. Three cases had evidence of MSI in at least 7/12 loci. None of the endometrium from the two other study groups revealed evidence of MSI. This is the first demonstration of MSI in blind endometrial biopsies. The ability to demonstrate MSI in heterogeneous endometrial samples suggests potential for the development of a novel EC screening tool for women in HNPCC kindreds.     

Clinical outcome and prognostic factors in 100 cases of uterine sarcoma: experience in Helsinki University Central Hospital 1990-2001

ObjectiveUterine sarcomas are rare malignant gynecological tumors with poor prognosis. In this study clinical data on all uterine sarcoma patients treated at Helsinki University Central Hospital (HUCH) between 1990–2001 were retrospectively evaluated.MethodsMedical records were reviewed and data collected on all uterine sarcomas treated during a 12-year period at HUCH. Kaplan–Meier survival curves were generated and those variables found to be statistically significant in univariate analysis were examined by multivariate analysis using Cox's proportional hazards regression model.ResultsOne hundred patients met the study requirements: 40 cases were diagnosed as carcinosarcomas, 39 as leiomyosarcomas and 21 as endometrial stromal sarcomas. First-line treatment was surgery in 98% of the patients. Seventy-eight of the patients were treated by means of adjuvant therapy. A complete response was achieved in 80% and a partial response in 4% of the cases. The 2-, 5- and 10-year overall survival rates were 62%, 51% and 38% and disease-specific survival rates were 64%, 56% and 44% (all sarcomas). In multivariate analysis, stage, age, tumor size and parity were proven to have independent influences on overall survival, and stage, tumor size and parity also independently influenced disease-specific survival.ConclusionsIn this study, survival rates were better than in nearly all previous retrospective studies of uterine sarcomas. It seems that higher parity could have a negative influence on survival in cases of uterine sarcoma.     

Crohn's Disease and Gynecologic Manifestations in Young Women

Study ObjectiveThe purpose of this study was to describe the reproductive and gynecological concerns of young women with Crohn's disease.Design, Setting, and ParticipantsRetrospective chart review of young women with Crohn's disease and gynecologic concerns at a large, urban tertiary children's hospital.InterventionsNone.Main Outcome MeasuresDocumentation of abnormal bleeding, pelvic pain, genital fistula, ulcer, or abscess.ResultsMost of the patients (85.7%) had menstrual concerns reported as abnormal bleeding patterns or chronic pelvic pain. Genital complaints (fistula, ulcer, or abscess) were present in 75% of patients who ultimately required immune modulators or antibiotics to control their Crohn's disease. Genital complaints were present in only 1 of 3 patients who did not have a history of immune modulator use for Crohn's disease related flare.ConclusionThere is a paucity of information available on gynecological concerns occurring in patients with Crohn's disease. Providers should be aware of gynecological manifestations that might appear concurrently with Crohn's colitis, including vulvovaginal pain, vulvar infections, rectovaginal or rectovestibular fistulas, pelvic pain, and menstrual irregularities.     

Unexpected uterine smooth muscle tumor of uncertain malignant potential and sarcoma: A single center cohort study in South Korea

ObjectiveTo evaluate the risk of encountering unexpected uterine smooth muscle tumors of uncertain malignant potential (STUMPs) or sarcomas during surgical treatment of mesenchymal tumors of the uterus using morcellation.Material and methodsData were collected retrospectively from subjects who were pathologically diagnosed with uterine leiomyoma or its variants, STUMP or other premalignant mesenchymal tumors of uterus, or sarcoma during surgical treatment between July 2014 and June 2017.ResultsA total of 3785 women were investigated; 2824 laparoscopic procedures (74.6%) were performed, and an electronic power morcellator was used in 1636 patients (43.2%). Sixteen women (0.42%) were diagnosed with STUMP and 14 (0.37%) were diagnosed with uterine sarcoma. The incidence rate of unexpected STUMP or uterine sarcoma was 0.61% (23 of 3785 women); unexpected STUMP in 13 (0.34%), and unexpected sarcoma was in 10 (0.26%). Moreover, the unexpected leiomyosarcoma rate was 0.08% (3 in 3785). The rate of unintended morcellation of STUMPs was relatively high at 0.26% (10 in 3785), however, that for uterine sarcomas was 0.05% (2 in 3785).ConclusionThe risks of unintended morcellation were very low for sarcomas and STUMPs, although the risk of the latter was approximately 5-fold that of the former. To reduce the unintended dissemination of tumors, patients suspected of having malignancies should be provided adequate information regarding their treatment options as well as their associated risks. Meanwhile, improved preoperative screening methods for STUMP and sarcoma should be established.     

No Evidence for Microsatellite Instability from Allelotype Analysis of Benign and Low Malignant Potential Ovarian Neoplasms

The genetic events that lead to the development of benign and low malignant potential (LMP) tumors from normal ovarian surface epithelium are not well understood. In contrast to invasive ovarian neoplasms, loss of heterozygosity (LOH) is not common in these tumors except on the X chromosome, but one report has suggested that an alternative genetic mechanism, microsatellite instability (MSI), might be an important pathogenic mechanism for LMP ovarian tumors.Objective.To determine the frequency of MSI in LMP tumors and to detect novel regions of LOH in benign and LMP ovarian tumors.Methods.Sixty-nine microsatellite markers were analyzed in 23 benign and 31 LMP ovarian tumors.Results.No evidence of MSI was found in any of the tumors studied, nor were any novel regions of LOH identified.Conclusions.This suggests that new approaches may be necessary to understand the genetic basis of benign and LMP ovarian neoplasms since neither LOH nor MSI appears to play a major role.     

Enhanced efficacy and specificity of epithelial ovarian carcinogenesis by embedding a DMBA-coated cloth strip in the ovary of rat

ABSTRACT: BACKGROUND: Ovarian cancer is predominant of epithelial cell origin and often present at an advanced stage with poor prognosis. Most animal models of ovarian carcinoma yield thecal/granulose cell tumors, rather than adenocarcinomas. The best reported induction rate of adenocarcinoma in rats is 10-45% by an ovarian implantation of 7, 12-dimethylbenz[a]anthracene (DMBA) coated silk suture. We provided an improved procedure to construct the model by the ovarian implantation of DMBA-coated cloth strip. METHODS: A sterile suture (as S group) or a piece of cloth strip (as CS group) was soaked in DMBA before ovarian implantation in Wistar rats. Tumor size, incidence rate and pathological type were analyzed. RESULTS: Ovarian tumors in rats of CS group were first noted at 16 wk post implantation and reached a cumulative incidence of 75% (96/128) at 32 wk, while the tumor incidence rate in S group at 32 wk was only 46.25% (37/80). The tumor size in CS group (3.63 [PLUS-MINUS SIGN] 0.89 cm) was larger than that of S group (2.44 [PLUS-MINUS SIGN] 1.89 cm) (P < 0.05). In CS group, there were only two types of tumor formed: adenocarcinoma (90/96) and sarcoma (6/96). While in S group, there were different types, including adenocarcinoma (21/37), squamous carcinoma (3/37), granulosa cell tumor (3/37), sarcoma (4/37), undifferentiated carcinoma with no adeno character (2/37), benign ovarian tumor (2/37), and malignant teratoma(1/37). CONCLUSION: The model in our study yields much higher incidence and specificity of epithelial derived tumors and showed histological similarities to human ovarian cancers, which would be more suitable for therapeutic research.     

免疫检查点抑制剂在妇科恶性实体肿瘤中的研究进展

妇科恶性实体肿瘤严重威胁女性生命健康，晚期、复发性及转移性妇科肿瘤的放化疗等辅助治疗效果欠佳，预后较差。近年来，以免疫检查点抑制剂为主的免疫疗法在恶性实体肿瘤的治疗中显示出较好的疗效，也为妇科恶性实体肿瘤患者提供了新的治疗选择。但在传统含铂化疗失败行免疫检查点抑制剂单药治疗的效果仍然较差，可能与多周期化疗后患者受损的免疫系统难以发生有效的免疫应答有关。众多临床研究显示，将免疫检查点抑制剂应用前置和免疫检查点抑制剂联合含铂化疗方案可使晚期、复发性和转移性妇科恶性实体肿瘤的患者获益。综述免疫检查点抑制剂在妇科恶性实体肿瘤中的应用进展。     

Primary uterine Ewing sarcoma – A case report

ObjectiveEwing sarcoma is a type of neuroectodermal tumors (Ewing family of tumors-EFT) that mostly affect the bone or soft tissue. Primary uterine Ewing sarcoma is extremely rare.Case reportWe report a case of a primary uterine Ewing sarcoma in a 46-year-old patient, treated with total abdominal hysterectomy, and bilateral salpingo-oophorectomy and following adjuvant chemotherapy with 6 cycles of vincristine, doxorubicin, and cyclophosphamide, achieving complete remission for one year.ConclusionComplete resection for EFT is the first choice of treatment, regardless of their origins. Adjuvant chemotherapy or radiotherapy is mandatory if needed. Due to rarity of the disease, this report re-emphasizes the accurate diagnosis and appropriate treatment for these unusual tumor types occurred in female genital organs.     

The Psychometric Properties of the Midlife Women’s Symptom Index

ObjectiveTo evaluate the psychometric properties of the Midlife Women’s Symptom Index (MSI) among four racial/ethnic groups of midlife women in the United States.DesignA secondary data analysis.SettingInternet communities/groups.ParticipantsA total of 494 midlife women with symptoms of menopause who self-reported using an Internet survey and completed all sections of the MSI questionnaire.MethodsData were collected from January 1, 2008 to December 31, 2010. The psychometric properties of the MSI were evaluated using measures of internal consistency, item-total correlation coefficients, and discriminant validity.ResultsThere were statistically significant differences in marital status, employment, income, religion, country of birth, level of education, diagnosed disease, and self-reported health status across the four racial/ethnic groups. The Kuder-Richardson Formula 20 (KR-20) coefficients for the three subscales of the MSI prevalence section (i.e., physical, psychological, and psychosomatic) ranged from 0.58 (psychosomatic symptoms in Whites) to 0.91 (psychological symptoms in Asian Americans). The Cronbach’s alpha coefficients for the three subscale scores ranged from 0.60 (psychosomatic symptoms in Whites) to 0.93 (psychological symptoms in Asian Americans). The mean scores of the MSI differed significantly by race/ethnicity among midlife women of each menopausal status, except for the prevalence section of the psychosocial symptoms.ConclusionThe MSI has demonstrated an acceptable reliability and appropriate discriminant validity across the four racial/ethnic groups, except in the domain of psychosomatic symptoms. Health care providers as well as researchers could use the MSI to assess the symptoms of menopause of midlife women from diverse racial/ethnic backgrounds.     

Polymerase ε (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro

Objective

Up to 12% of all endometrial-carcinomas (EC) harbor DNA-polymerase-ε-(POLE) mutations. It is currently unknown whether the favorable prognosis of POLE-mutated EC is derived from their low metastatic capability, extraordinary number of somatic mutations thus imparting immunogenicity, or a high sensitivity to chemotherapy.

Neopterin as an indicator of immune activation and prognosis in patients with gynecological malignancies

Malignant tumors may contribute to host response that involves both the adaptive and innate immune systems. Among other biochemical indicators of systemic immune and inflammatory activity, activation of macrophages by interferon-gamma induces a marked increase in the production of neopterin. Neopterin production by activated macrophages is also associated with tryptophan degradation. In addition to tumors of other primary locations, increased urinary and serum neopterin concentrations have been reported in patients with gynecological cancers, including epithelial ovarian carcinoma, cervical carcinoma, endometrial carcinoma, uterine sarcomas, and vulvar carcinoma, but not in women with benign neoplasms or precancerous disorders. Increased neopterin concentrations have been associated with poor prognosis. Elevated levels of neopterin have also been observed in the tumor microenvironment. Systemic (urinary or serum) or local (ascitic fluid) neopterin concentrations increased after therapeutic administration of cytokines. Elevated neopterin concentrations have been associated with anemia of chronic disease and increased urinary zinc loss in patients with gynecological malignancy. Elevated neopterin has also been connected with depressed function of peripheral blood lymphocytes and a decrease in CD4+ T-cell numbers.     

Stereotactic body radiotherapy for pelvic boost in gynecological cancer patients with local recurrence or unsuitable for intracavitary brachytherapy

ObjectiveTo evaluate efficacy of stereotactic body radiotherapy (SBRT) for pelvic boost irradiation in gynecological cancer patients with pelvic recurrence or with intact uterus unsuitable for brachytherapy.Materials and methodsWe retrospectively reviewed the medical records of 25 gynecological cancer patients who received SBRT boost for pelvic recurrence (salvage group, n = 14), or for local dose escalation instead of intracavitary brachytherapy due to unfavorable medical condition (definitive group, n = 11). The pelvis was irradiated with a median dose of 54 Gy in six weeks, and then SBRT was prescribed with a range of 10–25Gy in two to five fractions. The cumulative radiobiological equivalent dose in 2-Gy fractions (EQD2) to the tumors ranged from 62.5 to 89.5 Gy₁₀ (median, 80.7). Overall survival (OS) and in-field relapse-free survival (IFRFS) were calculated using the Kaplan–Meier method.ResultsAt the initial assessment, eighteen (72%) patients achieved complete or partial remission, and seven (28%) had stable or progressive disease. With a median follow duration of 12 months, the 1-year IFRFS for salvage and definitive group were 64.5% and 90.0%, whereas the 1-year OS for the two groups were 80.8% and 49.1%, respectively. One patient developed entero-vaginal fistula and one had sigmoid perforation. No patient experienced ≧ grade 3 genitourinary complications.ConclusionIn gynecological cancer patients with recurrent pelvic tumors or intact uterus unsuitable for brachytherapy, local dose escalation with SBRT resulted in an initial response rate of 72% with acceptable early toxicities. A long-term follow-up is required to assess the impact on local control or survival.     

Body mass index: relationship to clinical, pathologic and features of microsatellite instability in endometrial cancer

OBJECTIVES: There is a well known association between obesity and endometrial cancer. We sought to examine the relationships between body mass index (BMI), as a measure of obesity, and known demographic, clinical, and molecular characteristics of microsatellite instability and MLH1 promoter methylation in a cohort of patients with endometrial cancer. METHODS: Corpus cancer specimens were prospectively obtained from 473 consecutively enrolled patients between 1992 and 2004. Clinical and pathologic data were extracted from review of the medical record. Microsatellite instability (MSI) was evaluated in all tumors, and methylation of the MLH1 promoter was determined for MSI positive tumors. RESULTS: The median (SD) age and BMI were 64.8 years (11.9) and 33.5 (9.4), respectively. Histology included 376 endometrioid (79%), 69 serous/clear cell or mixed (15%), and 28 sarcomas (6%). Median BMI was 32.4 for endometrioid, 31.0 for serous/clear cell or mixed, and 27.8 for sarcomas (p=0.14). BMI was negatively associated with age at surgery (p<0.01). The remainder of analyses excluded sarcoma histology. BMI was associated with stage of disease; patients with stage I/II disease had significantly higher BMI than those with stage III/IV disease (32.6 vs. 30.6; p=0.02). In relation to molecular features of endometrial cancer, BMI was significantly different between MSI positive tumors compared to MSI negative tumors (30.3 vs. 32.7; p=0.02). MSI was also significantly different between tumor histology, occurring with a higher frequency in Type I than Type II tumors (p<0.01). CONCLUSIONS: The majority of endometrial cancer patients are obese. Those with higher BMI are more likely to be younger, present with early stage disease, and have MSI negative tumors.     

Co-existence of three rare gynecological tumors in a 79-year-old woman

The occurrence of two primary tumors simultaneously is relatively common. However, the occurrence of three kinds of gynecological tumors simultaneously is extremely rare. Here we presented a 79-year-old woman who had simultaneously three primary gynecological tumors which were relatively uncommon. Those tumors were myxoid leiomyosarcoma and endometrial mucinous adenocarcinoma in the uterus and a Leydig cell tumor in the right ovary. Uterine myxoid leiomyosarcoma is a very rare and aggressive variant of uterine sarcoma despite of its minimal even no atypia and a little mitotic activity. Mucinous endometrial adenocarcinoma is also a rare subtype which comprise only 0.6–5% of uterine cancers. Leydig cell tumor is a very rare ovarian tumor which is composed entirely or predominantly of Leydig cell.     

Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition

ObjectiveThere is an immunoreactive subtype of ovarian cancer with a favorable prognosis, but the majority of ovarian cancers have limited immune reactivity. The reason for this is poorly understood. This study aimed to approach this question by identifying prognostically relevant genes whose prognostic mRNA expression levels correlated with a genomic event.MethodsExpression microarray and 5-year survival data on 170 ovarian tumors and aCGH data on 45 ovarian cancer cell lines were used to identify amplified/deleted genes associated with prognosis. Three immune-response genes were identified mapping to epigenetically modified chromosome 6p21.3. Genes were searched for roles in epigenetic modification, identifying KANSL1. Genome-wide association studies were searched to identify genetic variants in KANSL1 associated with altered immune profile. Sensitivity to HDAC inhibition in cell lines with KANSL1 amplification/rearrangement was studied.ResultsExpression of 196 genes was statistically significantly associated with survival, and expression levels correlated with copy number variations for 82 of them. Among these, 3 immune-response genes (HCP5, PSMB8, PSMB9) clustered together at epigenetically modified chromosome 6p21.3 and their expression was inversely correlated to epigenetic modification gene KANSL1. KANSL1 is amplified/rearranged in ovarian cancer, associated with lymphocyte profile, a biomarker for response to HDAC inhibition, and may drive expression of immune-response genes.ConclusionThis study identifies 82 genes with prognostic relevance and genomic alteration in ovarian cancer. Among these, immune-response genes have correlated expression which is associated with 5-year survival. KANSL1 may be a master gene altering immune-response gene expression at 6p21.3 and drive response to HDAC inhibitors. Future research should investigate KANSL1 and determine whether targeting it alters the immune profile of ovarian cancer and improves survival, HDAC inhibition, and/or immunotherapy response.     

Uterine carcinosarcoma associated with pelvic radiotherapy for sacral chordoma: a case report

ObjectivePostirradiation sarcoma of the female genital tract is rare, but a recognized event. Most reported cases have been associated with history of radiotherapy for various gynecologic conditions, particularly cancer of the uterine cervix and abnormal uterine bleeding. The occurrence of uterine sarcoma secondary to radiotherapy for a non-gynecologic tumor and, furthermore, this condition being simultaneous with the recurrence of primary tumor is unique.Case ReportA 67-year-old woman presented with a uterine mass which was diagnosed as a sarcoma by endometrial curettage and history of pelvic radiotherapy 23 years previously for sacral chordoma. Surgical staging procedure for uterine malignancy was performed. The final pathologic diagnosis was carcinosarcoma of the uterus.ConclusionIn uterine masses seen in patients with history of irradiation to the pelvic field, the probability of uterine sarcomas should always be kept in mind. These tumors may occur simultaneously with recurrence of primary tumor previously treated by adjuvant radiation therapy.     

Improved maturation competence of ovarian tissue oocytes using a biphasic in vitro maturation system for patients with gynecological malignancy: a study on sibling oocytes

Purpose

To investigate the developmental competence of ovarian tissue oocytes from patients with gynecological tumors using a biphasic in vitro maturation system with capacitation (CAPA-IVM) in comparison with standard IVM.

Methods

This sibling pilot study included 210 oocytes in 10 patients with gynecological malignancies. After ovariectomies, ovaries were cut into even halves and immature cumulus-oocyte complexes (COCs) were retrieved from the ovarian tissue. COCs were separately cultured in either a biphasic CAPA-IVM system for 53 h or in standard IVM for 48 h. After IVM, all COCs were denuded and mature oocytes were either vitrified (N=5) or used for ICSI (N=5). Embryos were cultured for 5–6 days and obtained blastocysts were vitrified.

Results

Use of the CAPA-IVM system led to a higher meiotic maturation rate in ovarian tissue oocytes (OTO) compared to standard IVM (56 vs 35%, p=0.0045) and had a tendency to result in lower degeneration after IVM. Only the CAPA-IVM method supported blastocyst formation.

Conclusions

The biphasic in vitro maturation system improved the competence of OTO in comparison to the standard IVM method. The study suggests that fertility preservation programs could become more efficient using IVM after capacitation culture.

     

Leiomyoma of the Vulva: Case Report

BackgroundLeiomyoma of the vulva is rare, accounting for only 0.03% of all gynecological tumors, and it is seldom seen in teenagers.CaseWe describe a case of vulvar leiomyoma in a 14-year-old girl who presented a 10 × 10 cm solid tumor in the right hemivulva without other complaints.Summary and ConclusionDifferential diagnosis includes Bartholin cysts, abscesses, fibromas, and other solid lesions. Although rare, vaginal leiomyoma must be remembered and included as a differential diagnosis for solid lesions in the vagina.