Adult ovarian granulosa cell tumors: analysis of outcomes and risk factors for recurrence.

OBJECTIVE: Adult granulosa cell tumors represent less than 5% of all ovarian malignancies. The aim of this study was to analyze the clinicopathological parameters and their impact on progression-free and overall survival. METHODS: Patients with primary adult granulosa cell tumors treated in three international referral centers between July 1999 and December 2018 were included. The following data were anonymously exported from the prospective database: age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, adjuvant therapy, surgical procedures, progression-free survival, and overall survival. Descriptive statistical analysis regarding tumor and treatment characteristics was performed. Survival analyses included Kaplan-Meier functions and Cox proportional hazard ratios (HR). RESULTS: A total of 168 patients with primary adult granulosa cell tumors were included. Median age was 50 years (range 13-82). With regard to stage distribution, 54.2% (n=91) of patients were FIGO stage IA, 1.2% (n=2) were stage IB, 26.8% (n=45) were stage IC, and 17.9% (n=30) were FIGO stage II-IV. 66.7% (n=112) of patients underwent surgical restaging, of whom 17.9% (n=20) were moved to a higher stage. In addition, 36 (21.4%) patients underwent fertility-sparing surgery. After a median follow-up of 61 months (range 0-209), 10.7% of patients (n=18) had recurrent disease and 4.8% (n=8) died of disease. Five-year progression-free survival was 86.1% and estimated overall survival was 95.7%. Five-year progression-free survival was worse for patients with advanced stages (FIGO stage IA/B vs IC: HR 5.09 (95% CI 1.53 to 16.9); FIGO stage IA/B vs II-IV: HR 5.62 (95% CI 1.58 to 19.9)). Nineteen patients receiving adjuvant chemotherapy had lower estimated 5-year progression-free survival compared with patients not receiving chemotherapy (49.7% vs 91.1%, p<0.001; HR 9.15 (95% CI 3.62 to 23.1)). CONCLUSION: The prognosis of patients with primary adult granulosa cell tumors is mainly determined by FIGO stage. The outcome of patients with FIGO stage IC is comparable to those with advanced stages. Fertility-sparing surgery seems to be a safe procedure in stage IA. Our data do not support the use of adjuvant chemotherapy in early and advanced stages of adult granulosa cell tumors.

Role of inhibin B in detecting recurrence of granulosa cell tumors of the ovary in postmenopausal patients.

INTRODUCTION: Several biomarkers have been proposed for the detection of recurrences in adult-type granulosa cell tumors of the ovary. Here we validate the value of inhibin B in detecting recurrences and investigate its role in guiding follow-up examinations and treatment strategies in postmenopausal patients with ovarian adult-type granulosa cell tumors. METHODS: Data from 140 patients with a diagnosis of adult-type granulosa cell tumor of the ovary referred to the European Institute of Oncology of Milan from January 1996 to March 2016 were retrospectively collected. Among these, we selected data from 47 postmenopausal women for whom serial inhibin B measurements and related imaging examinations were performed according to the follow-up program, with a total of 315 serum inhibin B samples, together with the corresponding clinical examination, and 180 imaging examinations, confirming the presence or absence of macroscopic disease. RESULTS: At a cut-off of 7 pg/mL, inhibin B levels were significantly correlated with the presence/absence of disease (p<0.01), with a sensitivity of 98.8% (95% confidence interval (CI) 95.8% to 99.9%) and a specificity of 88.9% (95% CI 82.6% to 93.5%). Further, inhibin B was positively correlated with the size of the lesion, and levels were significantly higher in patients with larger lesions also at a cut-off size of 3 cm (total diameter). Logistic regression showed that 15.6 pg/mL, 44.6 pg/mL, and 73.6 pg/mL inhibin B corresponded to 25%, 50%, and 75% probability of having an abnormal computer tomography scan, respectively. CONCLUSIONS: Our results confirmed that inhibin B is a sensitive and specific marker for adult-type granulosa cell tumors of the ovary that may be used during follow-up for detection of recurrences. Moreover, it could guide clinicians in the decision regarding when to perform imaging, avoiding redundant interventional tests in the absence of clinical suspicion.

Ultrasonographic diagnosis and longitudinal follow-up of recurrences after conservative surgery for borderline ovarian tumors.

BACKGROUND: Borderline ovarian tumors are generally diagnosed in young women. Because of the young age of patients at first diagnosis and at recurrence, and given the good prognosis of borderline ovarian tumors, a conservative surgical approach in those women who wish to preserve their fertility is advised. In this scenario, transvaginal ultrasound examination plays a key role in the detection of borderline ovarian tumor recurrence, and in assessment of amount of normal functioning parenchyma remaining. To date, no data are available about the natural history of borderline ovarian tumor recurrence. OBJECTIVE: The aim of the study was to determine growth rate of recurrent ovarian cysts by a scheduled follow-up by ultrasound examination, in women previously treated with fertility-sparing surgery due to borderline ovarian tumors. STUDY DESIGN: In this prospective observational study, we collected data from 34 patients previously treated with fertility-sparing surgery due to borderline ovarian tumors, who had a suspicious recurrent lesion. The patients underwent transvaginal ultrasonographic examination every 3 months, until the clinical setting recommended proceeding with surgery. According to cyst size at study entry, they were categorized into 3 groups: ≤10 mm, 10-20 mm, and >20 mm. Summary statistics for cyst size, growth rate, and the probability of remaining within the same dimension category at first ultrasound during the follow-up were also obtained. For each cyst the growth rate was calculated as the slope of the linear interpolation between 2 consecutive measurements. RESULTS: Follow-up timing (P < .001), cyst size (P < .001), and micropapillary pattern (P < .001) were factors significantly affecting the cyst growth both in univariate and multivariate analysis. According to size category at first ultrasound, growth rate ranges from a minimum of 0.06 mm/mo for cysts <10 mm up to 1.92 mm/mo for cysts >20 mm. The final histology of all recurrent lesions confirmed the same histotype of primary borderline ovarian tumors. CONCLUSION: This article represents the first observational study that describes the trend in the growth rate of borderline ovarian tumor recurrence in relation to their size detected at the first ultrasound examination. The findings of this study seem to confirm, in selected patients, that a thorough ultrasonographic follow-up of borderline ovarian tumor recurrence has proven to be safe and feasible. The final goal of such management is to maximize the impact on fertility potential of these young women without worsening their prognosis.

Adult granulosa cell tumours of the ovary.

PURPOSE OF REVIEW: Adult ovarian granulosa cell tumours (AGCTs) are the most common sex cord-stromal tumours. Although the prognosis is generally favourable, recurrent or advanced AGCT shows poor prognosis. An overview of the main findings on the management of AGCT published recently is provided. RECENT FINDINGS: Novel biomarkers, including FOXL2, SMAD3 and GATA4, have been identified as potential diagnostic and therapeutic targets for this type of tumour. Interesting therapeutic implications are also emerging from studies on preclinical models, supporting the possible activity of anti-vascular endothelial growth factor A therapy for the treatment of AGCTs. Further, potentially active drugs could be targeting agents directed against epidermal growth factor receptor and/or insulin growth factor receptor-1. Recent data confirmed the importance of surgery in the management of AGCTs, in which hysterectomy can be avoided in young patients, as a recent study demonstrated that the risk of endometrial cancer after salpingo-oophorectomy for AGCT, with negative endometrial evaluation, is lower than the risk of endometrial cancer in the general population. SUMMARY: The present review highlights current challenges and future directions in the treatment of AGCTs.Optimization of existing treatment modalities and the addition of novel drugs may hopefully lead to improved oncologic outcomes.

Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients.

Women with ovarian cancer have limited therapy options, with immunotherapy being unsatisfactory for a large group of patients. Tumor cells spread from the ovary or the fallopian tube into the abdominal cavity, which is commonly accompanied with massive ascites production. The ascites represents a unique peritoneal liquid tumor microenvironment with the presence of both tumor and immune cells, including cytotoxic lymphocytes. We characterized lymphocytes in ascites from patients with high-grade serous ovarian cancer. Our data reveal the presence of NK and CD8+ T lymphocytes expressing CD103 and CD49a, which are markers of tissue residency. Moreover, these cells express high levels of the inhibitory NKG2A receptor, with the highest expression level detected on tissue-resident NK cells. Lymphocytes with these features were also present at the primary tumor site. Functional assays showed that tissue-resident NK cells in ascites are highly responsive towards ovarian tumor cells. Similar results were observed in an in vivo mouse model, in which tissue-resident NK and CD8+ T cells were detected in the peritoneal fluid upon tumor growth. Together, our data reveal the presence of highly functional lymphocyte populations that may be targeted to improve immunotherapy for patients with ovarian cancer.

Hysterectomy for cervical intraepithelial neoplasia: A retrospective observational multi-institutional study.

OBJECTIVE: To analyze the clinical management, the outcomes, and the trend in hysterectomy rates (HR) in patients who underwent this procedure for cervical intraepithelial neoplasia (CIN). METHODS: Multicentric retrospective observational study conducted on 242 patients who underwent hysterectomy for CIN between 2010 and 2020 in nine Italian institutions. Hysterectomy for invasive or micro-invasive neoplasia, sub-total hysterectomy, or trachelectomy were excluded. RESULTS: A significant increase in the trend of HR for CIN was recorded (P = 0.002, r = 0.81; C.I. 95%: 0.415-0.949); HR increased from 0.46% in the year 2010 to 3.32% in 2020. The mortality rate was 0.4%, and 5% had operative complications. On definitive histopathology examination, a CIN of any grade was recorded in 71.5% of cases, and an occult invasive cancer in 1.24%. No pathology or CIN1 was found in 26.8% of cases, suggesting over treatment. During follow-up, a vaginal lesion was recorded in 5% of cases. CONCLUSION: A significant increase in the number of hysterectomies performed for CIN in the last 10 years was recorded. Hysterectomy for CIN can lead to complications, risk of the onset of vaginal lesions, and risk of overtreatment, and remains, in the first instance, an unacceptable treatment, to be proposed only after adequate counseling.

Blue eyes as a risk factor for type 1 diabetes.

BACKGROUND: A high frequency of blue eyes and fair skin are reported in northern European Caucasians with type 1 diabetes (T1D). Also there is an inverse relationship between latitude and T1D incidence. We determined whether iris colour and skin pigmentation are risk factors in a Caucasian population living in two Mediterranean regions located at the same latitude with higher ultraviolet B irradiance, but with different T1D incidence. METHODS: We studied iris colour in 281 consecutive subjects with T1D and 298 controls. Skin type was evaluated by melanin quantification. RESULTS: In Lazio, blue eyes and fair skin type are significantly more common in T1D subjects than in controls (21 versus 9%, p = 0.002; 50 versus 35%, p < 0.001, respectively). In Sardinia, the frequency of blue eyes in T1D subjects is twice that in controls (5.8 versus 2.6% and significantly higher when compared to the expected calculated frequency in the entire population). By logistic regression analysis, only blue eyes are independent and significant predictors of T1D [odds ratio for blue eyes = 2.2; 95% confidence interval (1.1-4.4), p = 0.019]. CONCLUSIONS: As previously shown in a Caucasian population from northern Europe, blue eyes and a trend for fair skin increase the risk for T1D also in a Caucasian population born and residing in a Mediterranean region (Continental Italy). This finding may be relevant for explaining different T1D incidence as prevalence of blue eyes differ substantially between northern and southern European Caucasians.

What do European women know about their female cancer risks and cancer screening? A cross-sectional online intervention survey in five European countries.

OBJECTIVES: Informed decisions about cancer screening require accurate knowledge regarding cancer risks and screening. This study investigates: (1) European women's knowledge of their risk of developing breast, ovarian, cervical or endometrial cancer, (2) their knowledge about mammography screening and (3) whether an evidence-based leaflet improves their knowledge. DESIGN: Cross-sectional online intervention survey. SETTING: National samples from five European countries (Czech Republic, Germany, UK, Italy and Sweden)-drawn from the Harris Interactive and the Toluna panel, respectively, in January 2017-were queried on their knowledge of age-specific risks of developing breast, cervical, ovarian or endometrial cancer within the next 10 years and of mammography screening before and after intervention. PARTICIPANTS: Of 3629 women (inclusion criteria: age 40-75 years) invited, 2092 responded and 1675 completed the survey (response rate: 61.4%). INTERVENTION: Evidence-based leaflet summarising information on age-adjusted female cancer risks, mammography and aspects of cancer prevention. PRIMARY OUTCOME MEASURES: Proportion of women (1) accurately estimating their risk of four female cancers, (2) holding correct assumptions of mammography screening and (3) changing their estimations and assumptions after exposure to leaflet. FINDINGS: Across countries, 59.2% (95% CI 56.8% to 61.6%) to 91.8% (95% CI 90.3% to 93.0%) overestimated their female cancer risks 7-33 fold (mediansacross tumours: 50.0 to 200.0). 26.5% (95% CI 24.4% to 28.7%) were aware that mammography screening has both benefits and harms. Women who accurately estimated their breast cancer risk were less likely to believe that mammography prevents cancer (p<0.001). After leaflet intervention, knowledge of cancer risks improved by 27.0 (95% CI 24.9 to 29.2) to 37.1 (95% CI 34.8 to 39.4) percentage points and of mammography by 23.0 (95% CI 21.0 to 25.1) percentage points. CONCLUSION: A considerable number of women in five European countries may not possess the prerequisites for an informed choice on cancer screening. Evidence-based information in patient leaflets can improve this situation.

Neoadjuvant chemotherapy in cervical cancer: an update.

The role of neoadjuvant chemotherapy (NACT) has been investigated in order to improve prognosis of patients with locally advanced cervical cancer. According to a meta-analysis, NACT followed by radiotherapy may be detrimental with a low dose of cisplatin and longer cycle intervals. Some meta-analyses showed NACT followed by surgery resulted in a reduction in the risk of death by 35% with a gain of 14% in the 5-year survival compared with radiotherapy. In a Cochrane meta-analysis, overall survival and progression-free survival were significantly improved with NACT followed by surgery versus surgery alone (23% reduction in the risk of death). The platinum/paclitaxel combination is now the preferred regimen in the neoadjuvant setting and preliminary data indicate that dose-dense regimens are feasible and effective (overall response rate: 67.8-87%). A weekly regimen with carboplatin/paclitaxel before chemoradiation showed promising results and the INTERLACE ongoing trial will help to confirm whether additional short-course chemotherapy given weekly before chemoradiation will lead to an improvement in overall survival.

Assessment of type 1 diabetes risk conferred by HLA-DRB1, INS-VNTR and PTPN22 genes using the Bayesian network approach.

BACKGROUND: Determining genetic risk is a fundamental prerequisite for the implementation of primary prevention trials for type 1 diabetes (T1D). The aim of this study was to assess the risk conferred by HLA-DRB1, INS-VNTR and PTPN22 single genes on the onset of T1D and the joint risk conferred by all these three susceptibility loci using the Bayesian Network (BN) approach in both population-based case-control and family clustering data sets. METHODOLOGY/PRINCIPAL FINDINGS: A case-control French cohort, consisting of 868 T1D patients and 73 French control subjects, a French family data set consisting of 1694 T1D patients and 2340 controls were analysed. We studied both samples separately applying the BN probabilistic approach, that is a graphical model that encodes probabilistic relationships among variables of interest. As expected HLA-DRB1 is the most relevant susceptibility gene. We proved that INS and PTPN22 genes marginally influence T1D risk in all risk HLA-DRB1 genotype categories. The absolute risk conferred by carrying simultaneously high, moderate or low risk HLA-DRB1 genotypes together with at risk INS and PTPN22 genotypes, was 11.5%, 1.7% and 0.1% in the case-control sample and 19.8%, 6.6% and 2.2% in the family cohort, respectively. CONCLUSIONS/SIGNIFICANCE: This work represents, to the best of our knowledge, the first study based on both case-control and family data sets, showing the joint effect of HLA, INS and PTPN22 in a T1D Caucasian population with a wide range of age at T1D onset, adding new insights to previous findings regarding data sets consisting of patients and controls <15 years at onset.

A comparison of three different entry techniques in gynecological laparoscopic surgery: a randomized prospective trial.

OBJECTIVE: Laparoscopic entry techniques vary and still remain debated. We conducted a randomized control trial to compare three entry techniques. STUDY DESIGN: Women aged 18-70 years, nominated for laparoscopic surgery at University of Rome Campus Bio-Medico, were randomized into three different groups: Veress needle (VER), Direct trocar insertion (DIR) and Open technique (OP). For each group, minor complications (extra-peritoneal insufflation, trocar site bleeding, omental injury and surgical site infection), failed entry and time of entry of the main trocar were evaluated. Major complications were also considered. Between-group comparisons were performed using chi-square test. Significance P value was <0.05. RESULTS: A series of 595 consecutive procedures were included: 193 in the VER group, 187 in the DIR group and 215 in the OP group. Minor complications occurred in 36 cases: extraperitoneal insufflation (n=6) in the VER group only, site bleeding (n=2 in the VER group, n=2 in the DIR group and n=1 in the OP group), site infection (n=5 in the VER and n=6 in OP group), and omental injury (n=6 in the VER group and n=3 in the DIR group). Failed entry occurred in 4 cases of the VER group and 1 case of the DIR group. Mean time of entry was 212.4, 71.4 and 161.7s for the VER, DIR and OP groups respectively. Among major complications, one bowel injury resulted following the Veress technique. CONCLUSIONS: In our series, DIR and OP entry presented a lower risk of minor complications compared with VER. In addition, time of entry was shorter in DIR than with OP entry.