Management of bilateral malignant ovarian germ cell tumors: a MITO-9 retrospective study.

OBJECTIVES: Bilaterality is rare in malignant ovarian germ cell tumors (MOGTs). The bilateral ovarian involvement represents a critical issue when diagnosed in young women desiring to preserve fertility. The aim of this study was to evaluate clinical characteristic and management of patients bilateral MOGTs. METHODS: Patients affected by bilateral MOGT and treated at MITO group centers were reviewed. RESULTS: In 145 patients with MOGTs, 5.5% were bilateral. Three patients were affected by dysgerminoma (associated with bilateral gonadoblastoma in 1), 2 by immature teratoma, 2 by mixed germ cell tumors, and 1 by embryonal carcinoma. International Federation of Gynecology and Obstetrics stage was 3 IB, 1 IC, 3 IIIC, and 1 IV. Three patients received radical surgery, and the patient with dysgerminoma associated with gonadoblastoma received bilateral adnexectomy. Four patients received fertility-sparing surgery; 2 patients received unilateral salpingo-oophorectomy and contralateral cystectomy; in 2 patients, the ovaries were completely transformed in neoplastic tissue; suspecting a contralateral dysgerminoma histology, a unilateral salpingo-oophorectomy and contralateral biopsy were performed, and the contralateral neoplastic ovary was left unresected. Six patients received adjuvant chemotherapy. Seven patients are disease free after a median follow-up of 54 months. The patient affected by embryonal carcinoma died of disease. Two patients resumed menstruation, and one had a pregnancy. A compromised ovarian function was found in 2 patients, and they were addressed to oocyte cryopreservation. CONCLUSIONS: Bilateral MOGTs have a good prognosis. In dysgerminoma histology, residual disease could be left to spare fertility. An oncological and reproductive function follow-up is recommended.

External validation of the endometriosis fertility index (EFI) for predicting spontaneous pregnancy after surgery: further considerations on its validity.

BACKGROUND/AIMS: The revised American Society for Reproductive Medicine classification of endometriosis has a limited predictive value for pregnancy after surgery. A tool for predicting spontaneous pregnancy or pregnancy following assisted reproduction technology (ART) represents a clinical need. This study aimed to (i) provide an external validation of the EFI score in predicting pregnancy in infertile Italian endometriosis women; (ii) evaluate the predictive value of EFI score on ART outcome for patients who previously attempted to spontaneously conceive after surgery. METHODS: In 104 women with endometriosis, EFI score was calculated based on a prospective database data. Cumulative pregnancy rates curves were calculated using Kaplan-Meier (K-M) product limit estimate and log-rank test was used to evaluate differences between EFI groups. A receiver operating characteristic (ROC) curve was plotted for EFI as a predictor of ART outcome. RESULTS: Differences in time to non-ART pregnancy for the six EFI groups were statistically significant (log-rank, p = 1.4 × 10(-4)). The area under the curve (AUC) for EFI as ART outcome predictor was 0.75 (95% CI 0.61-0.89, p = 6.2 × 10(-3)), while the best cut-point for pregnancy was 5.5. CONCLUSION: The EFI score is a reliable scoring system to predict non-ART and ART pregnancy outcome after surgery for endometriosis.

Fertility preservation in female cancer patients: a single center experience.

Advances in cancer treatment allow women to be cured and live longer. However, the necessary chemotherapy and radiotherapy regimens have a negative impact on future fertility. Oncofertility has emerged as a new interdisciplinary field to address the issue of gonadotoxicity associated with cancer treatment and to facilitate fertility preservation, including oocyte and ovarian tissue cryopreservation. These fertility issues are often inadequately addressed, and referral rates to oncofertility centers are low. The aim of this study was to report the 3-year experience of the San Raffaele Oncofertility Unit. A total of 96 patients were referred to the Oncofertility Unit for evaluation after the diagnosis of cancer and before gonadotoxic treatment between April 2011 and June 2014. Of the 96 patients, 30 (31.2%) were affected by breast cancers, 20 (20.8%) by sarcomas, 28 (29.2%) by hematologic malignancies, 13 (13.5%) by central nervous system cancers, 3 (3.1%) by bowel tumors, 1 (1.0%) by Wilms' tumor, and 1 (1.0%) by a thyroid tumor; 47 (49.0%) were referred for oocyte cryopreservation before starting chemotherapy, 20 (20.8%) were referred for ovarian tissue cryopreservation, and 29 (30.2%) were not recruited. The mean time between the patients' counseling and oocyte retrieval was 15 days (range, 2-37 days). The mean time between the laparoscopic surgery and the beginning of treatment was 4 days (range, 2-10 days). The number of patients who were referred increased over time, whereas the rate of patients who were not recruited decreased, showing an improvement in referrals to the Oncofertility Unit and in the patients' counseling and understanding. Our results indicate that an effective multidisciplinary oncofertility team is necessary for prompt referrals and treatment.

Reproductive function assessment after surgery plus chemotherapy for germ cell ovarian tumors (MOGCT): novel clues deriving from the field of fertility preservation.

Germ cell ovarian tumors (malignant ovarian germ cell tumors - MOGCT) affect young women and are treated by surgery plus chemotherapy. It is well known that cytotoxic treatment may accelerate depletion of the primordial follicle pool leading to impaired fertility and premature menopause. Aim of this study is to identify patient candidates for fertility preservation strategies. We report our experience in preservation of fertility for four patients affected by MOGCT, referred to San Raffaele Hospital Oncofertility Unit. All patients received fertility sparing surgery plus platinum-based chemotherapy. Two patients were affected by mixed germ cell tumors and two by disgerminomas. After 24 months from the end of treatment, serum AMH levels have been measured. We report lower serum anti-Mullerian hormone (AMH) levels in our patients than in healthy general population as serum AMH levels were under the 25th age-specific percentiles. Fertility preservation, in terms of oocytes cryopreservation, was offered to those two patients with serum AMH levels predictive of significantly poor ovarian reserve (1st and 2nd patients). Using the gonadotropin releasing hormone (GnRH) antagonist protocol for ovarian stimulation, we obtained two and six oocytes, respectively. Therefore, serum AMH, as a marker of ovarian function, can improve the identification of patients that need to be referred to fertility preservation strategies.

Recurrent granulosa cell tumors (GCTs) of the ovary: a MITO-9 retrospective study.

OBJECTIVE: Optimal treatment of recurrent GCTs is unknown. The aim of this study was to evaluate the characteristics of recurrent GCTs. METHODS: Data on 35 recurrent GCTs were reviewed. RESULTS: Initial FIGO stages were: 11 IA, 11 IC, 6 Ix, 1 IIB, 5 IIIC and 1 IV. All patients had undergone primary surgical treatment, and in 8 cases adjuvant chemotherapy was given. The median RFS was 53.2 months with differences between patients receiving (72.5 months) and not receiving (48 months) adjuvant chemotherapy and between patients optimally staged (64.5 months) or not staged (47 months). Recurrence sites were: pelvic, 13; abdominal, 6; lymph-nodal, 2; pelvic+abdominal, 7; abdominal+lymph-nodal, 4; and pelvic+lymph-nodal, 3. Twenty-five patients underwent debulking surgery+chemotherapy, 6 surgery, 2 surgery+radiotherapy, 1 chemotherapy and 1 palliation. 69% completed the chemotherapy. No difference was found in OS among patients receiving or not receiving chemotherapy after secondary surgery at recurrence and among the different relapse sites. Eleven patients developed a second relapse after a median time of 38 months. 81.8% had received adjuvant therapy at first recurrence. Four patients underwent surgery, 4 surgery+chemotherapy, 1 surgery+radiotherapy and 2 palliation. Four patients developed a third recurrence after a median time of 41 months. Two patients received chemotherapy and 2 hepatic resection. Nine patients (25.7%) died of disease. 5y-OS from the first recurrence was 55.6% and 87.4% for patients with or without residual tumor at subsequent debulking surgery, respectively. CONCLUSIONS: In GCTs surgery remains the cornerstone treatment at relapse. RFS was higher in patients who received adjuvant therapy after initial diagnosis, with no difference in OS.

Ovarian Sertoli-Leydig cell tumors. a retrospective MITO study.

OBJECTIVE: To evaluate clinicopathologic features and to investigate the outcome of patients with ovarian Sertoli-Leydig cell tumors (SLCTs). METHODS: Data concerning 21 patients treated in 11 MITO centers were retrospectively reviewed. RESULTS: Median age was 37 (range 16-76). FIGO stage was: 17 (81%) IA, 1 (4.8%) IC, 1 (4.8%) IIB and 2 (9.5%) IIIC. Five patients (23.8%) had G1 tumor, ten (47.6%) had G2, and six (28.6%) had G3. Fertility-sparing operation was performed in 11 patients, while hysterectomy with bilateral salpingo-oophorectomy was executed in 10 patients; five patients received adjuvant chemotherapy (G2-3). Seven patients (33.3%) relapsed with a median time to recurrence of 14 months. Six recurrent patients had G2-3 disease, while one had G1. Four patients had stage IA disease, one IC and 2 stage IIIC. Patients with stage IA disease did not receive adjuvant chemotherapy. Two patients had pelvic recurrence, 4 abdominal (one with lymph nodal involvement), one on the contralateral ovary and the trocar access. Five patients underwent salvage surgery plus chemotherapy, while one received only salvage chemotherapy and one palliation. Five patients died of disease, four had received first treatment not in a MITO center. 5 year overall survival was 100% for patients with G1 disease and 77.8% for G2-3. 5 year overall survival was 92.3% for stage I and 33.3% for stage>I. CONCLUSIONS: The prognosis of patients with grade 1 SLCT is excellent without adjuvant chemotherapy. Patients with advanced stage or grade 2-3 tumors appear to benefit from postoperative chemotherapy.

Outcome and risk factors for recurrence in malignant ovarian germ cell tumors: a MITO-9 retrospective study.

AIMS: This study aimed to investigate the outcome of patients with malignant ovarian germ cell tumors (MOGCTs) and to define the risk factors for recurrence. METHODS: A total of 123 patients with MOGCTs were retrospectively reviewed among MITO centers. Eighty-one patients had primary treatment in a MITO center, whereas the other 42 were referred for adjuvant chemotherapy or recurrence. The clinicopathologic characteristics were evaluated for association with relapse or death. RESULTS: Median age was 24 years (range, 11-76 years). Forty-nine (39.8%) had dysgerminomas, 35 (28.5%) had immature teratomas, 12 (9.8%) had mixed germ cell tumors, 26 (21.1%) had yolk sac tumors, and 1 (0.8%) had embryonal carcinoma. International Federation of Gynecology and Obstetrics stage distribution was as follows: stage I, 87 (70.7%); stage II, 3 (2.4%); stage III, 29 (23.6%); and stage IV, 4 (3.3%). Fertility-sparing surgery was performed in 92 patients, whereas the remaining 31 received radical surgery; 65.8% of patients received adjuvant chemotherapy. Recurrence rate was 17.8% and the median time to recurrence was 9 months. Univariate and multivariate analyses showed that patient age (>45 years) and treatment outside a referral (MITO) center were the most important predictors of recurrence. The 5-year overall survival rate was 88.8%, with a median follow-up of 61 months. Univariate and multivariate analyses demonstrated that stage greater than I and yolk sac tumors were independent poor prognostic indicators. CONCLUSIONS: This study confirms that MOGCTs have excellent prognosis, with 5-year overall survival rates of 95.6% and 73.2% in stage I and advanced stages, respectively. Age older than 45 years and treatment not in a referral center are independent risk factors for recurrence, whereas stage greater than I and yolk sac histology are independent poor prognostic indicators.

Characteristics and outcomes of fetuses with laterality defects are the current outcomes better? A single center study.

Objective: To analyze the more recent outcomes of fetuses with different laterality defects.Material and methods: Out of 1508 fetuses with congenital heart disease (CHD) diagnosed by echocardiography between January 1995 and December 2015, 94 (6.3%) presented abnormal visceroatrial situs: 42 till December 2002 (group 1, analyzed retrospectively) and 52 since then until December 2015 (group 2, analyzed prospectively). Twenty-one had left isomerism (Lisom), 22 right isomerism (Risom), 16 situs inversus- dextrocardia (SVI-dx), 5 situs inversus- levocardia (SVI-levo), and 30 situs solitus-dextrocardia (SSol-dx).Results: Seventy-six cases (81%) had CHD, more frequently complex atrioventricular defect. Eighteen cases showed normal heart: half of subgroups SVI-dx and SVI-levo, a third of SSol-dx. Postoperative mortality in continuing pregnancy in group 2 was 43.7 versus 40% in group 1, lower in SVs-dx (0 versus 50%) and Lisom (33.3 versus 66.7%), worse in Risom (71.4 versus 25%). Total mortality in group 2 was 48.3 versus 55% in group 1, better in Ssol-dx (37.5 versus 50%) and in Lisom (27.4 versus 71.4%). In isolated forms all but one case are alive.Conclusions: Our fetal cases presented a relevant mortality in both periods. The outcomes were slightly better in a more recent era in SSol and Lisom.What is known about this topic?Out of laterality defects, the heterotaxies (i.e. left and right isomerism) are known to be associated to a relevant mortality in fetal and neonatal cases.Heterotaxies have a variable position of the heart, but some authors evaluated only those with dextrocardia in their studies on different laterality defects.Controversial data are presented in the literature for the outcomes of fetuses with laterality defects. Many large studies analyzed the data of a very long time period in which it is opinable to compare the results of the treatment, because of a recent improved management and surgical techniques.What does this study add?Our study presents an experience of a single center with cases of different types of laterality defects observed during a routine fetal echocardiography, not only heterotaxies.The knowledge of different laterality defects and of their characteristics (association with cardiac and extracardiac anomalies or with normal heart) is useful for the prenatal counseling.We compare the postoperative and total mortality in more recent period (since 2003) with respect to the previous era (1995-2002).

Management of locally advanced cervical cancer in pregnancy: a case report.

BACKGROUND: Carcinoma of the cervix is the most common malignancy associated with pregnancy. In the first and second trimesters patients should receive the same treatment as is used in nonpregnant women and termination is advised. In selected cases neoadjuvant chemotherapy (NACT) could be proposed but only a few cases have been reported. CASE: A 27-year-old woman, gravida 1 para 0, at 15 weeks' gestation, was diagnosed with FIGO stage IB2 squamous cervical cancer. After refusing to terminate pregnancy, she was treated with neoadjuvant chemotherapy (cisplatin) starting at 18 weeks. A cesarean section with radical surgery was performed at 32 weeks and a healthy baby delivered. Four weeks later the patient started chemoradiation therapy. She relapsed 1 year after surgery and died when her child was 2 years old. CONCLUSION: NACT followed by radical surgery was an unsuccessful treatment in our patient; platinum-based chemotherapy was harmless to the child up to the last follow-up.

Does cytoreductive surgery followed by adjuvant chemo-radiotherapy decrease the risk of recurrence and death in stage III endometrial cancer?

INTRODUCTION: The optimal postoperative adjuvant treatment for stage III endometrial cancer (EC) is controversial. The aim of the study was to evaluate the impact of cytoreductive surgery (CRS) and adjuvant chemoradiotherapy (CRT) on relapse-free survival (RFS) and overall survival (OS) in stage III EC. METHODS: Data on 36 patients with stage III EC were reviewed. A review of the literature was performed. RESULTS: Median follow-up was 31 months (range 3-195). All patients underwent radical surgery with lymph nodes assessment in 29 (80.6%). The histologic specimen revealed 27 (75%) type I and 9 (25%) type II cancers staged IIIA, IIIB, IIIC1, and IIIC2 in 9 (25%), 3 (8.3%), 17 (47.2%), and 7 (19.5%) patients, respectively. At the end of surgery, 32 (88.9%) had no residual tumor. Eighteen (50%) patients were treated with CRT (50% with sandwich approach, 50% with concurrent chemotherapy [CT]), 4 (11.1%) patients received radiotherapy (RT), and 14 (38.9%) had multiagent CT. Four patients (11.1%) with a residual tumor larger than 1 centimeter after surgery died of disease. The 5-year median recurrent free survival (RFS) for CRT, RT, and CT was 69.1%, 37.5%, and 23.8%, respectively (p = 0.05); the 5-year OS for CRT, RT, and CT was 83%, 35.7%, and 25%, respectively (p = 0.023). Multivariate analyses showed residual tumor as independent predictor for recurrence and death. CRT showed a borderline significance on OS. CONCLUSIONS: Our study demonstrated that optimal cytoreduction is the most significant prognostic factor and adjuvant CRT seems to be associated with a significant decreased risk of recurrence in stage III EC.

The origin of endometriosis-associated ovarian cancer from uterine neoplastic lesions.

Endometriosis is a risk factor for type I epithelial ovarian cancer but an issue to be clarified is the site of origin of endometriosis associated ovarian cancer. Here we proposed that the uterus may be the organ of origin of ovarian endometrioid cancer associated with endometriosis. Thus, the first neoplastic transformation would characterize the uterine cells migrating in the pelvis via retrograde menstruation and they would implant secondarily on the ovary. Supporting this hypothesis, an higher incidence of synchronous precancerous and cancerous endometrial pathology in patients affected by ovarian endometrioid cancer associated with endometriosis was showed. Moreover, uterine endometrial type I carcinoma resembles endometriosis associated endometrioid ovarian cancer in behavior and prognosis. This hypothesis is also supported by epidemiologic evidence showing a protective effect for tubal ligation and oral contraceptive use for endometriosis associated endometrioid ovarian cancer. Endometriosis and endometrioid ovarian carcinoma might represent two distinct biological entities characterized by the same organ of origin (the uterus), the same pathogenetic mechanism (transtubal reflux) and the same target organ (the ovary). By shifting the early events of ovarian carcinogenesis to the endometrium, prevention approaches as salpingectomy/tubal ligation and intervention at uterine corpus level may play an important role.

Timing should no longer be an obstacle to oocyte cryopreservation in patients with cancer.

PURPOSE: Anticancer treatment-related infertility is preventable with oocyte cryopreservation, but this is often not considered a relevant issue, due to lack of knowledge and time. The aim of this study is to prove that adequate organization of an Oncofertility Unit and the use of new protocols for controlled ovarian stimulation (COS) can reduce the time required by the procedure, encouraging consultants and patients to preserve fertility before gonadotoxic treatments. METHODS: A total of 125 patients diagnosed with malignant tumors were referred to the Oncofertility Unit of San Raffaele Hospital: 52 patients between April 2011 and October 2013 and 73 patients between October 2013 and November 2015. The 2 periods differ in office organization and type of COS protocol used. RESULTS: Between the 2 periods, a reduction in the mean number of days required from first counseling to the initiation (6.45 ± 1.058 vs 1.61 ± 0.228) and the end of the COS (17.83 ± 1.227 vs 13.70 ± 0.393) was observed (p<0.0001). No differences exist in the groups between the mean time required to complete COS (11.38 ± 0.360 vs 12.17 ± 0.309; p = 0.11) and mean number of frozen oocytes (8.458 ± 1.060 vs 10.30 ± 0.919; p = 0.22). Furthermore, in the second period, the number of patients who accepted fertility preservation increased (46.15% vs 64.38%; p<0.05). CONCLUSIONS: Renewed organization of the Oncofertility Unit and the newest random-start COS protocol allowed us to shorten the time for oocyte cryopreservation and start anticancer treatment on time.

Hyperreactio luteinalis: timely diagnosis minimizes the risk of oophorectomy and alerts clinicians to the associated risk of placental insufficiency.

Hyperreactio luteinalis (HL) is a rare benign condition complicating pregnancy with multicystic bilateral ovarian enlargement, increased serum ßhCG levels and spontaneous regression after delivery. HL has been associated with complications of pregnancy and the aim of our research was to review the literature, and add a new unpublished case from our group. We searched the internet-based medical databases for case reports and case series of hyperreactio luteinalis and we evaluated diagnostic path, treatment and outcome of pregnancies. We found 96 cases of HL from 1955 to 2013. HL was asymptomatic in 28% of cases but in 72% of patients there were symptoms like lower abdominal pain, nausea and vomiting, ascites and signs of virilization. Suspicion of malignancy was raised in 38% of cases. Surgical treatment of various types was performed in 48% of cases, with oophorectomy in 40% of this group. Several complications were associated with HL, in particular preeclampsia (PE) occurred in 24% of cases and fetal growth restriction (FGR) in 12%. Mean gestation at delivery was 35 weeks (range 25-42). Although preoperative diagnosis occurred in most cases, suspicion of malignancy was extensive, as was oophorectomy, demonstrating suboptimal understanding of the underlying physiopathology. We propose a diagnostic algorithm for this condition. Training of obstetricians in making the correct diagnosis may prevent unnecessary oophorectomies and may lead to early diagnosis and correct management of associated complications.

High-grade endometrial cancer: value of [(18)F]FDG PET/CT in preoperative staging.

OBJECTIVE: The purpose of this study was to assess the value of 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([F]FDG PET/CT) in the primary staging of high-risk endometrial cancer patients. METHODS: This retrospective study was conducted on 32 consecutive patients with histological diagnosis of primary high-risk endometrial cancer, who underwent PET/CT with [F]FDG in addition to conventional clinical and instrumental staging procedures. After surgery, [F]FDG PET/CT findings were correlated with pathological findings on a patient-by-patient basis. The diagnostic accuracy of [F]FDG PET/CT for primary cancer detection, lymph nodal involvement and distant metastases was assessed. RESULTS: [F]FDG PET/CT could correctly detect primary tumor in 29 of the 32 high-risk patients, with a sensitivity of 90.6%. The overall [F]FDG PET/CT patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 57.1, 100.0, 100.0, 86.4, and 88.5%, respectively, for revealing lymph nodal neoplastic involvement, and 100.0, 96.0, 87.5, 100.0, 96.9%, respectively, for detecting distant metastases. In particular, while the suspicion of distant metastases was documented by conventional imaging in only two patients, [F]FDG PET/CT correctly identified metastatic lesions in seven patients (21.9% of cases). CONCLUSION: The major benefit provided in high-grade tumor patients by the use of [F]FDG PET/CT in the primary staging of endometrial cancer is its ability to accurately detect distant metastases in the abdomen and extra-abdominal regions. [F]FDG PET/CT adds relevant information that may influence patient management.