Purpose: Full-length vaginal (FLV) brachytherapy for patients with endometrial cancer and high-risk features should be considered as per the American Brachytherapy Society to reduce distal vaginal recurrence in patients with endometrial cancers with papillary serous/clear cell histologies, grade 3 status, or extensive lymphovascular invasion. We sought to investigate this patient population and report outcomes of treatment with high-dose-rate (HDR) brachytherapy in women treated with FLV brachytherapy versus partial-length vaginal (PLV) brachytherapy. Methods and materials: With institutional review board approval, we identified patients with endometrial cancer meeting American Brachytherapy Society criteria of high-risk features treated with adjuvant HDR between 2004 and 2010. HDR doses were 21Gy in 3 fractions delivered to either the full-length or partial-length vagina. Acute and late toxicities were evaluated using the Radiation Therapy Oncology Group scale and Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer grading, respectfully. Vaginal recurrences were assessed by physical examination and pap smears. Statistical analyses were performed using SPSS version 23 software. Results: Of 240 patients treated with HDR brachytherapy, 121 were treated with FLV brachytherapy, and 119, with PLV brachytherapy. The median follow-up was 9.5 years (range, 8-11 years) for FLV patients and 8.5 years (range, 7-10 years) for PLV patients; 0% of patients had vaginal recurrences, and 1.4% and 0.9% had proximal vaginal recurrences, respectively (P = .54). All patients treated with FLV brachytherapy developed grade 3 mucositis of the lower vagina/introitus (P < .0001) and had increased analgesics use compared with those treated with PLV brachytherapy (P < .0001). In total, 23% of patients treated with FLV brachytherapy developed grade 3 stenosis of the lower vagina/introitus, in contrast to 0% of patients treated with PLV brachytherapy (P < .0001). Conclusions: PLV brachytherapy is as effective as FLV brachytherapy in reducing local recurrence and causes a significantly lower incidence of acute and late toxicities. The results of this study caution radiation oncologists regarding the careful use of FLV brachytherapy in patients with endometrial cancer and high-risk features. Copyright (C) 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

OBJECTIVES:Investigate the use and outcomes of a surveillance only strategy for patients with high-risk stage I malignant ovarian germ cell tumors.METHODS:Patients with International Federation of Gynecology and Obstetrics stage IA/IB grade 2 or 3 immature teratoma, yolk sac, or mixed germ cell tumor diagnosed between 2004 and 2014 who had at least 1 month of follow-up were drawn from the National Cancer Database. Overall survival (OS) was evaluated for each histologic subtype using Kaplan-Meier curves, and compared with the log-rank test.RESULTS:A total of 497 patients were identified; 115 (23.1%) with grade 2 immature teratoma, 157 (31.6%) with grade 3 immature teratoma, 101 (20.3%) with yolk sac tumor, 124 (25%) with mixed germ cell tumor. Rate of adjuvant chemotherapy was 68.2% (655 patients), while rate of lymph node biopsy/dissection was 55.2%. A total of 19 (3.8%) deaths were observed at a median of 29.8 months. There was no difference in OS between patients who did and did not receive adjuvant chemotherapy with grade 2 (P=0.35) and grade 3 immature teratoma (P=0.47) or mixed germ cell tumors (P=0.55). Patients with yolk sac tumors those who received chemotherapy had better OS compared with those who did not, P=0.019; 5-year OS rates were 92.7% and 79.6%, respectively.CONCLUSIONS:A surveillance only strategy for patients with stage I malignant ovarian germ cell tumors is associated with excellent survival outcomes for patients with grade 2 or 3 immature teratoma or mixed germ cell tumors.

In January 2019, a group of basic, translational, and clinical investigators and patient advocates assembled in Miami, Florida, to discuss the current state of the science of low-grade serous carcinoma of the ovary or peritoneum–a rare ovarian cancer subtype that may arise de novo or following a diagnosis of serous borderline tumor. The purpose of the conference was to review current knowledge, discuss ongoing research by established researchers, and frame critical questions or issues for future directions. Following presentations and discussions, the primary objective was to initiate future collaborations, uniform database platforms, laboratory studies, and clinical trials to better understand this disease and to advance clinical care outside the boundaries of single academic institutions. This review summarizes the state of the science in five principal categories: epidemiology and patient outcomes, pathology, translational research, patient care and clinical trials, and patients' perspective.

Objectives Stratified mucin producing intraepithelial lesion (SMILE) is an uncommon premalignant cervical intraepithelial lesion, characterized by histopathologic features resembling those observed in high grade squamous intraepithelial lesions and adenocarcinoma in situ of the cervix. Its hybrid morphology poses a pathologic challenge with no specific management guidelines. The goal of this study was to review the natural history of SMILE and treatment based outcomes. Methods A retrospective pathology review of all cases of cervical intraepithelial lesions, with confirmation of all SMILE lesions, at one institution between 2007 and 2019, was performed. Clinical and pathologic characteristics, management options, and patient outcomes were reviewed and analyzed. Inclusion criteria included all patients diagnosed initially with SMILE on biopsy, excisional procedure, or simple hysterectomy. Patients diagnosed with SMILE had to fulfill the following pathologic features: stratified columnar epithelium with nuclear atypia and mucin production throughout the epithelial thickness with increased mitotic activity, and/or apoptotic bodies. Pathologic slides were re-evaluated by a pathologist to confirm the diagnosis and review margin status. Results 24 patients with SMILE were identified. Mean age at diagnosis was 36.2 years (range 25–53) with 67% (16/24) diagnosed before the age of 40. The majority (54%, 13/24) were nulliparous and 63% (15/24) had a past history of abnormal Pap smears. 92% (22/24) of patients were positive for high risk human papillomavirus, with 13% (n=3) presenting with a normal Pap smear. Diagnosis was made primarily on colposcopy (n=16), cold knife cone/loop electrosurgical excision procedure (n=7), or hysterectomy (n=1). Most patients (71%, 17/24) had a co-existing precancerous lesion at the time of diagnosis and the most common was high grade squamous intraepithelial lesion (53%). Five invasive lesions were also identified at the time of diagnosis of SMILE (2 adenocarcinoma, 3 adenosquamous), 1 of which underwent chemoradiation. Among all patients, 25% (6/24) underwent hysterectomy (4 simple, 2 radical), while 63% (17/24) of patients underwent a fertility sparing excisional procedure; 4% (1/24) were incidentally diagnosed on hysterectomy. 18 patients had negative margins and 2 patients had positive margins. Over a median follow-up of 29 months (range 3–105), all of the fertility sparing patients with negative margins had no recurrence. Among the two patients with positive margins, one had no recurrence on repeat excision and the other underwent repeat excision with persistent SMILE identified, subsequent negative margin, and no recurrence since. Discussion Our data showed that most patients with SMILE were young, positive for high risk human papillomavirus, nulliparous, and presented with coexisting lesions. Excisional procedures with negative margins may be sufficient fertility sparing treatment in patients with preinvasive SMILE with a low risk of recurrence. There should be consideration of hysterectomy at the completion of childbearing.

Objective: Cascade testing for familial cancer syndromes has historically been difficult to execute. While probands disclose genetic results to more than 80% of at-risk relatives, less than 30% use recommended genetic services. As part of a facilitated cascade testing pathway, we evaluated barriers to completion of cascade testing.

Objective: Despite a growing understanding of familial cancer, multiple studies demonstrate that the quality of family health history as currently collected in a clinic setting is inadequate to assess disease risk. We sought to evaluate the quality of family health history in a gynecologic oncology clinic.

Objective: Cervical cancer in the setting of uterovaginal prolapse is exceedingly rare. Altered anatomy can complicate treatment of underlying cancer. The objective of this study was to evaluate the practice patterns and outcomes regarding cervical cancer associated with procidentia.

Objective: Ovarian cancer can evade immune responses by inducing endoplasmic reticulum stress in intratumoral leukocytes. In the ovarian tumor microenvironment, the endoplasmic reticulum stress-activated transcription factor X-box binding protein 1 (XBP1s) causes immune cell dysfunction and facilitates malignant progression. However, the clinical significance of XBP1s expression in ovarian cancer remains elusive. We sought to evaluate the association between intratumoral XBP1s levels and ovarian cancer patient outcomes.

Objective: E-cadherin is an important cell-cell adhesion molecule in epithelial tissues. Previous literature has demonstrated an association with E-cadherin deficiency and progression of different malignancies, including squamous cell carcinoma of the cervix. However, there have been no studies investigating the relationship between E-cadherin expression and adenocarcinoma in situ (ACIS) or adenocarcinoma (AC) of the cervix. We sought to determine whether E-cadherin immunohistochemistry (IHC) can be a valuable marker in screening for ACIS and AC.

OBJECTIVE:To investigate the clinicopathological characteristics and survival of patients with malignant ovarian carcinoid tumor (OC). MATERIALS AND METHODS:The National Cancer Database was accessed and patients diagnosed between 2004 and 2015 with a OC who did not have a personal history of a tumor at another site were selected. Overall survival (OS) was assessed for patients who had ≥1 month of follow-up. OS rates were estimated following generation of Kaplan-Meier curves and compared with the log-rank test. RESULTS:A total of 588 patients with a median age of 51.5 years were identified. The majority were White (71.6%), had unilateral tumors (94.2%) with a median size of 3.8 cm that were confined to the ovary (88%). Patients with early stage disease (n = 431) had excellent OS compared to those with advanced stage (II-IV) disease (n = 51), p < 0.001; 5-yr OS rates were 95.4% and 53.1% respectively. For patients with stage I disease, there was no difference in OS between those who did (n = 211) and did not (n = 175) have hysterectomy, p = 0.92. For patients with advanced stage disease, administration of adjuvant chemotherapy was not associated with better survival, p = 0.093. CONCLUSIONS:OCs are typically small, unilateral tumors confined to the ovary arising in perimenopausal patients. Survival outcomes are excellent for patients with early stage disease and unilateral salpingo-oophorectomy appears to be curative.

Fragestellung Um die Vorteile des genetischen Testens und der Krebsprävention vollständig zu nutzen, sind genetische Screens mittels Cascade testing auch auf Risikoverwandte (RV) auszuweiten. Momentan fehlen Standardmethoden und es findet sich wenig Literatur zur Nutzungsrate von genetischen Tests bei RV. Das Ziel dieser Studie war es, Methoden für Cascade testing und Testungsraten von RV in bisher publizierten Studien zu erheben.

Objective: The ultimate impact of genetic testing is the ability to identify relatives carrying the mutation before they develop cancer, maximizing disease prevention and early detection. However, there is a paucity of literature on quality of life (QOL) in this testing context. We sought to evaluate the QOL implications for at-risk relatives undergoing cascade testing.

The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databases between 1990 and 2018 identified studies of endometrial cancer patients with tumour testing (MMR protein immunohistochemistry or microsatellite instability) and germline assessment for Lynch syndrome. Extracted data included tumour testing, germline genetic testing, age, body mass index (BMI), family history, tumour stage, grade and histologic type. Associations between MMR-intact, MLH1 methylation positive, MMR-deficient and Lynch syndrome groups were analysed using descriptive statistics. The comprehensive search produced 4,400 publications, 29 met inclusion criteria. A total of 7,057 endometrial cancer cases were identified, 1,612 with abnormal immunohistochemistry, 977 with microsatellite instability. Nine-hundred patients underwent germline genetic testing, identifying 212 patients with Lynch syndrome. Patients in the Lynch syndrome and MMR-deficient groups were significantly younger than patients in the MMR-intact and MLH1 methylation positive groups. Patients with MMR-intact tumours had the highest BMI, followed by MMR-deficient, then Lynch syndrome. MMR-intact tumours were more likely to be grade I at diagnosis than other groups. Patients with Lynch syndrome and MMR-deficient tumours were less likely to have stage I disease as compared to patients with MMR-intact tumours. Endometrial cancer patients with MMR-deficient tumours have similar features to those with germline Lynch syndrome mutations, including age, grade, histology and stage. Even in the absence of a germline mutation, tumour evaluation for MMR status may have important clinical implications.

Objective: Cascade genetic testing is essential for identifying inherited cancer-associated mutation in at-risk relatives. However, the new diagnosis of a pathogenic mutation can lead to anxiety and distress, and strategies to mitigate this have not been well studied. We sought to evaluate immediate and long-term distress and anxiety among at-risk relatives found to have a pathogenic mutation on cascade genetic testing.

Objective Most studies evaluating the oncologic safety of minimally invasive surgery for endometrial cancer focus on patients with stage I disease. The aim of this study was to investigate the outcomes of minimally invasive surgery for patients with endometrial carcinoma involving the cervix. Methods Patients diagnosed between January 2010 and December 2015, with clinical stage II endometrial carcinoma, who underwent hysterectomy with lymphadenectomy, were drawn from the National Cancer Database. Inclusion criteria were clinical International Federation of Gynecology and Obstetrics (FIGO 2009) stage II, patients who underwent hysterectomy with lymphadenectomy, and known route of surgery (open or minimally invasive). Patients who received radiation therapy prior to surgery, those who had subtotal/supracervical hysterectomy, or unknown type of hysterectomy were excluded. The exposure of interest was performance of minimally invasive surgery either laparoscopic or robotic-assisted. Overall survival (primary endpoint) was assessed for patients diagnosed between January 2010 and December 2014 following generation of Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to control for confounders. Results A total of 2175 patients were identified and 1282 (58.9%) had minimally invasive surgery. Of these, 339 and 943 patients had laparoscopic or robotic-assisted laparoscopic hysterectomy, respectively. Minimally invasive surgery was converted to open surgery in 74 (5.8%) patients. Those undergoing minimally invasive surgery had shorter hospital stay (median 1 vs 3 days, p<0.001), lower unplanned readmission rate (2.7% vs 4.7%, p=0.014), and 90-day mortality (0.8% vs 1.8%, p=0.05). Patients who had open surgery (n=796) had worse overall survival compared with those who had minimally invasive surgery (n=1048, p=0.003); 3-year overall survival rates were 76.8% and 83.6%, respectively. After controlling for patient age, race, type of insurance, presence of co-morbidities, performance of extensive lymphadenectomy, presence of positive lymph nodes, tumor histology, presence of lymphovascular space invasion, tumor size, and administration of radiotherapy, performance of minimally invasive surgery was not associated with worse survival (HR 0.90, 95% CI 0.73 to 1.11). Conclusions In this retrospective analysis, minimally invasive surgery in patients with stage II endometrial carcinoma was associated with superior short-term peri-operative outcomes and improved 3-year overall survival.

BackgroundUniversal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer to identify those with underlying Lynch syndrome. However, the effectiveness of these screening methods in identifying individuals with Lynch syndrome across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), mutL homolog 1 (MLH1) methylation, and microsatellite instability (MSI) analysis among patients with endometrial cancer.MethodsA complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for 1990‐2018 was performed. A DerSimonian‐Laird random effects model meta‐analysis was used to estimate the weighted prevalence of Lynch syndrome diagnoses.ResultsThe comprehensive search produced 4400 publications. Twenty‐nine peer‐reviewed studies met the inclusion criteria. Patients with endometrial cancer (n = 6649) were identified, and 206 (3%) were confirmed to have Lynch syndrome through germline genetic testing after positive universal tumor molecular screening. Among 5917 patients who underwent tumor IHC, 28% had abnormal staining. Among 3140 patients who underwent MSI analysis, 31% had MSI. Among patients with endometrial cancer, the weighted prevalence of Lynch syndrome germline mutations was 15% (95% confidence interval [CI], 11%‐18%) with deficient IHC staining and 19% (95% CI, 13%‐26%) with a positive MSI analysis. Among 1159 patients who exhibited a loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation–negative among those who underwent methylation testing, and 32 demonstrated a germline MLH1 mutation (2.8% of all absent MLH1 staining cases and 22.4% of all MLH1 methylation–negative cases). Forty‐three percent of patients with endometrial cancer who were diagnosed with Lynch syndrome via tumor typing would have been missed by family history–based screening alone.ConclusionsDespite the widespread implementation of universal tumor testing in endometrial cancer, data regarding testing results remain limited. This study provides predictive values that will help practitioners to evaluate abnormal results in the context of Lynch syndrome and aid them in patient counseling.

There remains a need to differentiate between women with a benign or a malignant adnexal mass prior to surgery. As part of an ongoing evaluation of vaginal fluid compounds as potential tumor biomarkers we evaluated whether vaginal lysophosphatidic acid (LPA) predicted the subsequent diagnosis of a malignant adnexal mass. In this prospective pilot study vaginal fluid was obtained from 100 post-menopausal women referred for evaluation of a suspicious adnexal mass and tested for LPA by ELISA. Clinical data and serum CA125 results were obtained only after completion of all laboratory testing. Twenty eight of the women were subsequently diagnosed with an ovarian malignancy, four had a borderline tumor and 68 had a benign diagnosis. Among women with a malignant ovarian mass, 11 (39.3%) had an endometrioid adenocarcinoma +/− Clear cell tumor components, 6 (21.4%) had a high grade serous carcinoma, 3 (10.7%) had a mucinous tumor, 2 each (7.1%) had a malignant mixed mesodermal or a granulosa tumor and 1 each (3.6%) had a Clear cell tumor, a mixed cell tumor, leimyosarcoma or metastatic adrenal tumor. Compared to the median vaginal LPA level in women with benign lesions (1.5 μM), LPA was significantly elevated only in women with endometrioid ovarian cancer (7.9 μM) (p = 0.0137). Of the 6 endometrioid tumors in which values for both plasma CA125 and vaginal LPA were available 5 were positive only for LPA while one was only CA125 positive. Detection of LPA in vaginal secretions may be of value for the noninvasive diagnosis of endometrioid ovarian malignancies in post-menopausal women.

OBJECTIVE:To investigate the prognostic significance of complete gross resection following cytoreductive surgery for patients with advanced stage malignant ovarian germ cell tumors.METHODS:The National Cancer Data Base was accessed and patients diagnosed with an advanced stage (II-IV) malignant ovarian germ cell tumor who underwent primary cytoreductive surgery between 2011 and 2014 were selected for further analysis. For analysis purposes two groups were formed: patients with complete gross resection and those with macroscopic residual disease. Demographic and clinico-pathological characteristics were compared with the chi-square and Mann-Whitney U test. Univariate survival analysis was performed with the log-rank test after generation of Kaplan-Meier curves, while a Cox proportional hazard model was constructed to evaluate mortality after controlling for confounders.RESULTS:A total of 343 patients who met the inclusion criteria were identified. Residual disease status was available for 276 patients: the rate of complete gross resection was 69.2 %. By univariate analysis there was no difference in overall survival between patients in the complete gross resection and macroscopic residual disease groups, P= 0.26; 3-year overall survival rates: 86.4 % and 82.8 %, respectively. No difference in overall survival was noted following stratification by histology; P = 0.64 and P = 0.24 for dysgerminoma and non-dysgerminoma tumor groups. After controlling for stage IV disease, histology and the administration of chemotherapy, macroscopic residual disease was not associated with a worse mortality (HR: 1.22, 95% CI: 0.61 to 2.46).CONCLUSIONS:Macroscopic residual disease following primary cancer-directed surgery was not associated with a worse prognosis in a cohort of patients with advanced stage malignant ovarian germ cell tumors.