Stuart G. Salfinger

Ovarian Sex Cord-Stromal Tumors in Patients With Probable or Confirmed Germline DICER1 Mutations

The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Recent studies have demonstrated somatic mutations in DICER1 in approximately 60% of ovarian Sertoli-Leydig cell tumors. Furthermore, patients with germline mutations in DICER1 are predisposed to developing a range of rare neoplasms including ovarian sex cord-stromal tumors most of which have been classified as Sertoli-Leydig cell tumor. However, the histologic features of these tumors have not been reported in detail. We describe the morphologic and immunophenotypic findings of 4 sex cord-stromal tumors arising in patients with proven or likely germline DICER1 mutations including 3 individuals from 1 family. Three tumors showed similar appearances characterized by marked architectural and cytologic heterogeneity including sertoliform, juvenile granulosa cell tumor-like, and unclassifiable elements. The remaining case mainly showed heterologous mucinous epithelial and neuroendocrine differentiation with only a minor intermediate-grade Sertoli cell component. This tumor and one of the 3 former cases arose in related patients with identical germline DICER1 mutations indicating that additional factors influence tumor morphology. All tumors were positive for steroidogenic factor-1 and FOXL2 on immunohistochemical analysis, whereas there was more variable expression of inhibin, calretinin, CD56, CD99, and hormone receptors. The present small series suggests that some ovarian Sertoli-Leydig cell tumor associated with germline DICER1 mutations may show distinctive histologic features in particular admixed Sertoli cell and juvenile granulosa cell tumor-like features. Larger studies are required to establish whether heterologous elements are also a more common feature of these tumors.

Transtubal spread of endometrial carcinoma: correlation of intra-luminal tumour cells with tumour grade, peritoneal fluid cytology, and extra-uterine metastasis.

Aims: To assess the significance of intra-luminal tumour cells (ILTC) within the fallopian tubes of patients with endometrial carcinoma, with emphasis on high grade histological subtypes. Methods: Complete histological examination of fallopian tube tissue was performed in 36 low grade endometrioid adenocarcinomas and in a consecutive series of 226 high grade endometrial malignancies including 92 serous carcinomas, 64 grade 3 endometrioid carcinomas, 26 carcinosarcomas, 25 undifferentiated/dedifferentiated carcinomas, and 19 clear cell carcinomas. The presence of ILTC was correlated with peritoneal fluid cytology, histologically confirmed peritoneal tumour spread, and lymph node metastases. Results: ILTC were identified in 26% and 3% of high and low grade carcinomas, respectively. The presence of ILTC correlated strongly with positive peritoneal fluid cytology and with peritoneal metastasis in high grade tumours (both p < 0.001), and there was also a correlation with lymph node metastasis (p = 0.049). ILTC were more common in serous and undifferentiated carcinomas (>30%) but the differences between the high grade tumour subtypes were not statistically significant. Conclusions: These findings suggest that ILTC associated with high grade endometrial cancers have the capacity to implant and invade the peritoneal cavity. Positive cytology in such cases may be more significant than in low grade tumours. Complete tubal examination may provide additional prognostic information in high grade endometrial carcinoma.

Prevalence of sexual dysfunction after risk-reducing salpingo-oophorectomy.

OBJECTIVES To determine the prevalence of sexual dysfunction in women after risk-reducing salpingo-oophorectomy (RRSO) and to assess factors which may influence sexual wellbeing following this procedure. METHODS This work is a cross-sectional study of women who underwent RRSO at a tertiary gynecologic oncology unit between January 2009 and October 2014. Data collection involved a comprehensive questionnaire including validated measures of sexual function, sexual distress, relationship satisfaction, body image, impact of event, menopause specific quality of life, and general quality of life. Participants were invited to undergo blood testing for serum testosterone and free androgen index (FAI). RESULTS 119 of the 206 eligible women participated (58%), with a mean age of 52years. The prevalence of female sexual dysfunction (FSD) was 74% and the prevalence of hypoactive sexual desire disorder (HSDD) was 73%. Common sexual issues experienced included; lubrication difficulty (44%), reduced sexual satisfaction (41%), dyspareunia (28%) and orgasm difficulty (25%). Relationship satisfaction, the use of topical vaginal estrogen and lower generalized body pain were significantly associated with a decreased likelihood of sexual dysfunction. Serum testosterone, FAI, the use of systemic hormone replacement therapy (HRT), prior history of breast cancer, menopausal status at the time of surgery and hysterectomy did not correlate with sexual dysfunction. CONCLUSION The prevalence of FSD and HSDD after RRSO was 74% and 73% respectively. Relationship satisfaction, low bodily pain and use of topical vaginal estrogen were associated with a lower likelihood of sexual dysfunction. There was no correlation between serum testosterone or FAI, and sexual dysfunction.

The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy

OBJECTIVES Investigate the effects of pre-operative menopausal status and HRT use on sexual outcomes following risk-reducing salpingo-oophorectomy (RRSO). STUDY DESIGN Cross-sectional study of 119 women who underwent RRSO between 2009 and 2014. MAIN OUTCOME MEASURES Data was collected via a questionnaire and serum test for testosterone and free androgen index (FAI). The questionnaire comprised demographic data and validated measures of sexual function, sexual distress, relationship satisfaction, body image, psychological stress, menopause quality of life and general quality of life. RESULTS Rates of sexual issues were similar despite menopause status at operation. Women who were pre-menopausal at operation (mean age=44 years ± 5) had significantly higher rates of sexual distress (p=0.020), dissatisfaction with sex life (p=0.011) and bothersome sexual menopause symptoms (p=0.04) than women who were post-menopausal (mean age=55 years ± 7). Pre-menopausal women reported higher psychological distress from surgery (p=0.005) and poorer emotional (p=0.052) wellbeing. HRT use reduced the rates of dyspareunia (p=0.027) and the severity of sexual menopausal symptoms (p=0.030). Androgen levels were not significantly associated with desire or arousal scores. CONCLUSIONS Regardless of menopausal status at operation, women experienced the same sexual issues at equivalent rates. However, pre-menopausal women reported higher sexual distress and dissatisfaction with sex life. Pre-menopausal women also had greater psychological distress and poorer emotional function.

Discussing Sexuality With Women Considering Risk-Reducing Salpingo-oophorectomy: An International Survey of Current Practice in Gynecologic Oncology.

Objective To determine how frequently gynecologic oncologists discuss sexuality with women considering risk-reducing salpingo-oophorectomy. Secondary objectives were to assess the availability of resources, and the barriers to discussing sexuality. Methods Members of the Australian Society of Gynaecologic Oncologists, International Gynecologic Cancer Society, and Society of Gynecologic Oncology were invited to complete an online survey. Questions addressed frequency of, and barriers to, discussing sexuality, and availability of resources related to sexual issues. Results Three hundred eighty-eight physicians in 43 countries responded from 4,006 email invitations (9.7%). Ninety-one percent reported discussing sexuality preoperatively, and 61% discuss it with every patient. Factors associated with higher rates of discussion were female sex (P = 0.020), higher level of training (P = 0.003), time in practice (P = 0.003), and consulting more risk-reducing salpingo-oophorectomy patients per month (P = 0.006). Commonly discussed issues were vasomotor menopausal symptoms (91%) and vaginal dryness (85%). Eighty-eight percent of respondents believed that sexuality should be discussed preoperatively, and most felt that it is their responsibility (82%). Fear of causing distress was the most common barrier to discussing sexuality (49%). Twenty-four percent felt that they did not have adequate training to discuss sexual function. Conclusions Although most respondents believed that discussing sexuality should occur preoperatively, only 61% discuss this with every patient. Resources specifically relating to sexuality are limited. The most common barrier to discussing sexuality was fear of causing distress. Nearly one quarter of gynecologic oncologists felt inadequately trained to discuss sexual function.

The introduction and the validation of a surgical encounter template to facilitate surgical coaching of gynaecologists at a metropolitan tertiary obstetrics and gynaecology hospital

At a metropolitan tertiary obstetrics and gynaecology hospital some gynaecologists identified a need for surgical coaching. Full‐time specialists in a teaching hospital are expected to teach surgery whilst having limited access to improving their own surgical skills. Over time, this resulted in some degree of technical deskilling. This in turn led to a loss of confidence in their technical ability to perform complex procedures. The trainee was potentially taught surgery by gynaecologists who were not confident in some aspects of their own surgical skill.

Prognostic Role of Histological Tumor Regression in Patients Receiving Neoadjuvant Chemotherapy for High-Grade Serous Tubo-ovarian Carcinoma

Objective Our objective was to validate the prognostic role of the chemotherapy response score (CRS), which has been proposed for measuring tumor response to neoadjuvant chemotherapy in patients with high-grade serous tubo-ovarian carcinoma, in predicting progression-free survival (PFS) and overall survival (OS). Methods A retrospective cohort study was conducted of patients with advanced high-grade serous tubo-ovarian carcinoma diagnosed between January 1, 2010, and December 31, 2014, and treated with neoadjuvant chemotherapy. Treatment-related tumor regression was determined according to the 3-tier CRS, and results were compared with standard clinicopathological variables. Survival analysis was performed using Cox proportional hazards models and the log-rank test. Results Seventy-one patients were eligible for analysis. Median OS was 25.5 months. Fifty-eight patients (82%) had disease recurrence and 32 (45%) had died at study census. Of the 71 patients, 19, 29, and 23 patients had a CRS of 1, 2, and 3, respectively. On univariate analysis, the CRS significantly predicted PFS (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.83–7.78; P = 0.000) and OS (HR, 2.81; 95% CI, 1.16–6.79; P = 0.022). In a multivariate model, the CRS was significantly associated with PFS (HR, 2.81; 95% CI, 1.16–6.79; P = 0.022) but not with OS (HR, 2.39; 95% CI, 0.47–3.08; P = 0.079). Patients with CRS of 1 and 2 combined were twice as likely to progress during the study period compared with patients with a CRS of 3 (HR, 2.0; 95% CI, 1.06–3.78; P = 0.032; median PFS, 16 vs 26 months). No significant association was observed for OS (CRS 1/2 vs 3; HR, 1.57; 95% CI, 0.68–3.65; P = 0.291). Conclusions In this study, the CRS showed independent prognostic significance for PFS but not for OS.OBJECTIVE Our objective was to validate the prognostic role of the chemotherapy response score (CRS), which has been proposed for measuring tumor response to neoadjuvant chemotherapy in patients with high-grade serous tubo-ovarian carcinoma, in predicting progression-free survival (PFS) and overall survival (OS). METHODS A retrospective cohort study was conducted of patients with advanced high-grade serous tubo-ovarian carcinoma diagnosed between January 1, 2010, and December 31, 2014, and treated with neoadjuvant chemotherapy. Treatment-related tumor regression was determined according to the 3-tier CRS, and results were compared with standard clinicopathological variables. Survival analysis was performed using Cox proportional hazards models and the log-rank test. RESULTS Seventy-one patients were eligible for analysis. Median OS was 25.5 months. Fifty-eight patients (82%) had disease recurrence and 32 (45%) had died at study census. Of the 71 patients, 19, 29, and 23 patients had a CRS of 1, 2, and 3, respectively. On univariate analysis, the CRS significantly predicted PFS (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.83-7.78; P = 0.000) and OS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022). In a multivariate model, the CRS was significantly associated with PFS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022) but not with OS (HR, 2.39; 95% CI, 0.47-3.08; P = 0.079). Patients with CRS of 1 and 2 combined were twice as likely to progress during the study period compared with patients with a CRS of 3 (HR, 2.0; 95% CI, 1.06-3.78; P = 0.032; median PFS, 16 vs 26 months). No significant association was observed for OS (CRS 1/2 vs 3; HR, 1.57; 95% CI, 0.68-3.65; P = 0.291). CONCLUSIONS In this study, the CRS showed independent prognostic significance for PFS but not for OS.OBJECTIVE Our objective was to validate the prognostic role of the chemotherapy response score (CRS), which has been proposed for measuring tumor response to neoadjuvant chemotherapy in patients with high-grade serous tubo-ovarian carcinoma, in predicting progression-free survival (PFS) and overall survival (OS). METHODS A retrospective cohort study was conducted of patients with advanced high-grade serous tubo-ovarian carcinoma diagnosed between January 1, 2010, and December 31, 2014, and treated with neoadjuvant chemotherapy. Treatment-related tumor regression was determined according to the 3-tier CRS, and results were compared with standard clinicopathological variables. Survival analysis was performed using Cox proportional hazards models and the log-rank test. RESULTS Seventy-one patients were eligible for analysis. Median OS was 25.5 months. Fifty-eight patients (82%) had disease recurrence and 32 (45%) had died at study census. Of the 71 patients, 19, 29, and 23 patients had a CRS of 1, 2, and 3, respectively. On univariate analysis, the CRS significantly predicted PFS (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.83-7.78; P = 0.000) and OS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022). In a multivariate model, the CRS was significantly associated with PFS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022) but not with OS (HR, 2.39; 95% CI, 0.47-3.08; P = 0.079). Patients with CRS of 1 and 2 combined were twice as likely to progress during the study period compared with patients with a CRS of 3 (HR, 2.0; 95% CI, 1.06-3.78; P = 0.032; median PFS, 16 vs 26 months). No significant association was observed for OS (CRS 1/2 vs 3; HR, 1.57; 95% CI, 0.68-3.65; P = 0.291). CONCLUSIONS In this study, the CRS showed independent prognostic significance for PFS but not for OS.

Risk of persistent and recurrent cervical neoplasia following incidentally detected adenocarcinoma in situ

Background: Adenocarcinoma in situ of the uterine cervix is a precursor to cervical adenocarcinoma and may coexist with both adenocarcinoma and high‐grade squamous dysplasia (cervical intraepithelial neoplasia 2 and 3). Up to 60% of adenocarcinoma in situ lesions are detected incidentally following excisional biopsies performed for the treatment of cervical intraepithelial neoplasia 2/3. To date there are no data regarding risk factors for persisting or progressive cervical neoplasia in these patients. Objective: We sought to investigate patient outcomes following incidentally detected cervical adenocarcinoma in situ after loop electrosurgical excision procedure or cold knife cone biopsy performed for the treatment of high‐grade cervical intraepithelial neoplasia. Study Design: We conducted a retrospective, population‐based cohort study of Western Australian patients with an incidental diagnosis of adenocarcinoma in situ from 2001 through 2012. Primary outcomes were persistent or recurrent cervical intraepithelial neoplasia 2/3 and or adenocarcinoma in situ, and invasive adenocarcinoma during follow‐up (<12 months) and surveillance (≥12 months) periods. Results: The cohort comprised 298 patients, with 228 (76.5%) treated initially by loop electrosurgical excision procedure and 70 (23.5%) treated by cold knife cone biopsy. The mean age was 31.2 (range 18–68) years and the median length of follow‐up was 2.4 (range 0.3–12.2) years. Overall, 11 (3.7%) patients had cervical intraepithelial neoplasia 2/3, 23 (7.7%) had adenocarcinoma in situ, and 3 (1.0%) had adenocarcinoma diagnosed during the follow‐up and surveillance periods. Age >30 years, pure adenocarcinoma in situ lesions, and larger lesions (>8 mm) were associated with a greater risk of disease persistence or recurrence. Conclusion: Following the incidental detection of adenocarcinoma in situ, age >30 years, pure adenocarcinoma in situ lesions, and lesions >8 mm were significantly associated with disease persistence/recurrence. In younger women, incidentally detected adenocarcinoma in situ that coexists with cervical intraepithelial neoplasia 2/3 and is <8 mm extent with clear margins may not require reexcision.

Health-related quality of life and pelvic floor dysfunction in advanced-stage ovarian cancer survivors: associations with objective activity behaviors and physiological characteristics

PurposeLittle is known about the relationship between health-related quality of life (HRQoL), pelvic floor dysfunction (PFD), and modifiable lifestyle and physiological factors for ovarian cancer survivors (OCS). The primary aim of the study was to compare post-treatment advanced-stage OCS with age-matched controls on measures of HRQoL and PFD. The secondary aim was to examine associations between HRQoL, PFD, objective activity behaviors, physical function, and body composition in OCS.MethodsTwenty advanced-stage OCS and 20 controls completed questionnaires assessing HRQoL (SF-36) and PFD (Australian Pelvic Floor Questionnaire), and underwent objective assessments of activity behavior (7-day accelerometry), physical function (400-m walk, repeated chair rise, 6-m usual-pace walk, one-repetition maximum chest press, and single-leg extension), and body composition (dual-energy x-ray absorptiometry).ResultsCompared to controls, OCS had worse physical HRQoL (− 4.3 median difference, p = 0.013), but equivalent self-reported PFD, indicated by combined bladder, bowel, and pelvic organ prolapse symptoms (0.89 mean difference, p = 0.277). In OCS, physical HRQoL was significantly negatively associated with PFD (r = 0.468, p = 0.043). Decreased physical HRQoL and increased PFD were significantly associated with less moderate-to-vigorous physical activity in ≥ 10-min bouts (ρ = 0.627, p = 0.003; ρ = − 0.457, p = 0.049), more sedentary time (r = − 0.449, p = 0.047; r = 0.479, p = 0.038), and slower 400-m walk time (ρ = − 0.565, p = 0.022; ρ = 0.504, p = 0.028).ConclusionsPost-treatment advanced-stage OCS have decreased physical HRQoL, which is associated with modifiable factors such as worse PFD, less moderate-to-vigorous physical activity, more sedentary time, and decreased objective physical function. This highlights the need for ongoing supportive care and multidisciplinary interventions after first-line ovarian cancer treatment.

Activity behaviors and physiological characteristics of women with advanced-stage ovarian cancer: A preliminary cross-sectional investigation

Objectives Ovarian cancer (OC) survivors experience many disease and treatment adverse effects. However, the impact of OC and its treatment on objective activity behaviors and physiological status have not been examined. The purpose of this study was to compare objectively measured activity behaviors and physiological characteristics of advanced-stage OC survivors to age-matched controls. Methods Twenty stage III–IV OC survivors and 20 controls completed assessments of activity behaviors (7-day accelerometry), physical function (400-meter walk as indicator of cardiorespiratory fitness, repeated chair rise, 6-meter walking tests), muscle strength (1-repetition maximum and handgrip), body composition (dual-energy x-ray absorptiometry), and musculoskeletal morphology (peripheral quantitative computed tomography). Results Compared with controls, OC survivors spent more time/day in prolonged sedentary bouts (P = 0.039, r = 0.32), had lower cardiorespiratory fitness (P = 0.041, r = 0.33) and upper body strength (P = 0.023, r = 0.37), had higher areal bone mineral content (P = 0.047, r = 0.33) and volumetric trabecular density (P = 0.048, r = 0.31), but were not different in other measures of body composition nor in muscle morphology (P > 0.050). Only 20% (n = 4) of OC survivors accrued 150 minutes/week or greater moderate and vigorous physical activity (MVPA) time in 10-minute bouts or greater. Moderate and vigorous physical activity time/day in 10-minute bouts or greater was strongly associated with cardiorespiratory fitness (P = 0.001, ρ = −0.702) and lower extremity function (P = 0.019, ρ = −0.519) and moderately associated with muscle cross-sectional area (P = 0.035, ρ = 0.473). Conclusions Posttreatment OC survivors spent more time in prolonged sedentary bouts and had lower cardiorespiratory fitness and upper body strength compared with controls. Moderate and vigorous physical activity was associated with physical function and muscle cross-sectional area. Future studies should test the efficacy of exercise interventions to increase MVPA, reduce sedentary behavior, and increase cardiorespiratory fitness and muscle strength in OC survivors.