Jessica Ottolina

Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary

Objective:The aim of this study is to evaluate the long-term outcome of granulosa cell tumour (GCT) of the ovary in a large series of patients treated in MITO centres (Multicentre Italian Trials in Ovarian Cancer) and to define prognostic parameters for relapse and survival.Methods:A retrospective multi-institutional review of patients with GCTs of the ovary treated or referred to MITO centres was conducted. Surgical outcome, intraoperative and pathological findings and follow-up data were analysed. Kaplan–Meier and Cox proportional hazards analyses were used to determine the predictors for survival and recurrence.Results:A total of 97 patients with primary GCT of the ovary were identified. The median follow-up period was 88 months (range 6–498). Of these, 33 patients had at least one episode of disease recurrence, with a median time to recurrence of 53 months (range 9–332). Also, 47% of recurrences occurred after 5 years from initial diagnosis. At multivariate analysis, age and stage were independent poor prognostic indicators for survival; surgical treatment outside MITO centres and incomplete surgical staging retained significant predictive value for recurrence in both univariate and multivariate analyses.Conclusions:This study confirms the generally favourable prognosis of GCTs of the ovary, with 5-year overall survival approaching 97%. Nevertheless, prognosis after 20 years was significantly poorer, with 20-year survival rate of 66.8% and a global mortality of 30–35. These findings support the need for lifelong follow-up even in early-stage GCT.

Deep pelvic endometriosis negatively affects ovarian reserve and the number of oocytes retrieved for in vitro fertilization.

Objective. Endometriosis‐associated infertility results in reduced ovarian response, fewer oocytes available for fertilization, compromised oocyte quality and higher miscarriage rates. A consistent proportion of women with endometriosis require in vitro fertilization. We sought to clarify the impact of deep infiltrating pelvic disease on antral follicle count and ovarian response to follicle‐stimulating hormone (FSH) stimulation in patients with severe endometriosis. Design. Retrospective cohort study. Setting. University hospital. Population. Patients with severe endometriosis (stages III–IV; n=51) were divided into two groups regarding localization of endometriosis during surgical staging: ovarian (n=27) and both ovarian and deep infiltrating disease (n=24). Methods. A total of 73 long‐protocol ovulation induction cycles with recombinant FSH for an intracytoplasmic sperm injection program were given. On day 3 of the cycle, measurements of FSH and luteinizing hormone and an ultrasound evaluation of antral follicle count were performed. Main Outcome Measures. Number of oocytes collected at ovum pick up, number of mature oocytes, number of embryos transferred and clinical pregnancy rate. Results. Ovarian reserve in terms of antral follicle count was damaged in both groups but, if adjusted for age, it was significantly lower in the ovarian and pelvic infiltrating group compared with patients having only ovarian endometriosis. Pelvic deep infiltrating disease significantly impacted on the number of oocytes collected at pick up when adjusted for age. Conclusions. Deep infiltrating pelvic disease can negatively affect ovarian reserve in terms of antral follicle count and number of oocytes retrieved. Mechanisms underlying this phenomenon need to be elucidated.

Is the endometrial evaluation routinely required in patients with adult granulosa cell tumors of the ovary

OBJECTIVE Granulosa cell tumors (GCTs) are the most common estrogen-secreting ovarian tumors; perhaps due to the persistent hyperestrogenism, a wide spectrum of associated endometrial pathologies ranging from endometrial hyperplasia to carcinoma has been documented in patients with GCTs. The aim of this study is to evaluate the incidence of endometrial pathologies in a large series of GCT patients treated in MITO centers. METHODS A retrospective multi-institutional review of patients with granulosa cell tumors of the ovary treated or referred to MITO centers was conducted. Descriptive statistics were used to characterize the patient population and to assess the association of GCT and endometrial abnormalities at the time of diagnosis; multivariate regression analysis was also performed to identify independent predictors of endometrial abnormalities. RESULTS A total of 150 patients with primary adult GCT was identified. During the preoperative assessment, endometrial pathology was found in 35.9% of symptomatic patients and in 90.9% of asymptomatic women with endometrial thickening at transvaginal ultrasound. At the time of surgery, hyperplasia was documented in 29.2% of patients, whereas endometrial cancer occurred in 7.5% of patients. Almost all of the patients (97.6%) with endometrial hyperplasia were older than 40years. All patients with endometrial cancer were older than 40years and postmenopausal. CONCLUSIONS Endometrial carcinoma/atypical hyperplasia were commonly observed in GCT patients >40years; based on these data, endometrial sampling should be performed in symptomatic women at least 40years of age. In asymptomatic women <40years, endometrial sampling is of low yield.

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

Abstract 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. Chinese abstract 卵巢恶性生殖细胞肿瘤（MOGCT）好发于年轻女性，常用手术加化疗进行治疗。众所周知，化疗的细胞毒性作用会加速始基卵泡的消耗，导致生殖功能受损及过早绝经。本研究的目的是找出保留患者生育能力的策略。我们报道了对San Raffaele医院肿瘤生殖科的四位MOGCT患者保留其生育功能方面的体会。所有患者接受保留生育功能手术加以铂为基础的化疗方案。两名患者罹患混合性生殖细胞肿瘤，另两名为无性细胞瘤患者。治疗结束24个月后，测其血清AMH水平。我们发现患者的血清抗苗勒氏管激素（AMH）水平较健康人群低，其血清AMH水平低于不同年龄层的第25百分位数。对于血清AMH水平极低并因此预测到其卵巢功能显著受损的第一、二名患者，保存其生殖能力如卵母细胞冷冻保存。用促性腺激素释放激素（GnRH）拮抗剂方案促排卵，我们分别获得2个和6个卵母细胞。因此，血清AMH可作为监测卵巢功能的一项指标，提高我们对需要施行生育能力保存方案的患者的鉴别能力。

Coagulation Status in Women With Endometriosis

Subtle alterations in coagulation and fibrinolysis have been recently reported in patients with endometriosis supporting a potential hypercoagulable status associated with the disease. This cross-sectional study aimed at evaluating some variables of coagulation status and inflammatory markers in women with endometriosis. A total of 314 women who underwent surgery were considered. The case group (n = 169) included patients with a surgical diagnosis of endometriosis, at any stage of disease. The control group (n = 145) included women with a surgical diagnosis of benign gynecologic pathology. No difference was found for thrombin time, International Normalized Ratio (INR), platelet count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) between women with endometriosis and controls. Conversely, patients with endometriosis had significantly shortened activated partial thromboplastin time (APTT) when compared to controls (1.08 ± 0.06 and 1.12 ± 0.19, respectively; P < .01). In the subgroup analysis, women with ovarian endometriosis had significantly shortened APTT values in comparison to women without this form and women with stage I to II endometriosis had significantly shorter APTT values and higher PLR than those with stage III to IV disease. In multivariate logistic regression analysis, after controlling for potential confounders, a shortened APTT remained associated with the disease. Activated partial thromboplastin time is shorter in women with endometriosis but still in the normal range. The evidence is insufficient to foresee a possible use of APTT as a diagnostic marker and to claim a crucial role of a systemic hypercoagulable state in the origin of the disease. A role of the local coagulation system in the pathogenesis of the disease cannot be excluded.

Thoracic Endometriosis Syndrome: Association With Pelvic Endometriosis and Fertility Status

STUDY OBJECTIVE To evaluate associations among catamenial pneumothorax, pelvic endometriosis, and fertility status. DESIGN Retrospective study (Canadian Task Force classification II-2). SETTING Departments of Thoracic Surgery and Obstetrics and Gynecology, San Raffaele Hospital, Milan, Italy. PATIENTS Sixteen females referred to the Department of Thoracic Surgery for treatment of spontaneous pneumothorax between January 2001 and January 2014 and referred to the outpatient clinic for gynecologic follow-up. INTERVENTIONS Thoracoscopy for catamenial pneumothorax and laparoscopy for pelvic endometriosis. MEASUREMENTS AND MAIN RESULTS Characteristics of the patients, the presence of endometriosis, and their fertility status were statistically analyzed. Pelvic endometriosis was diagnosed in 9 patients (56.3%), but 6 patients did not undergo a laparoscopic procedure to confirm or exclude the disease. Seven of the affected patients (77.8%) had stage III-IV endometriosis. Two-thirds of the patients with pelvic endometriosis who attempted conception conceived spontaneously, as did all of the patients without histopathological confirmation of endometriosis. CONCLUSION Thoracic endometriosis syndrome, characterized mainly by catamenial pneumothorax, is a relevant condition in patients affected by endometriosis. However, few previous studies have analyzed this condition from a gynecologic standpoint, in terms of characteristics of endometriosis and fertility status of affected women. Our findings support the presence of a strong association between catamenial pneumothorax and pelvic endometriosis, as well as a minimal effect of catamenial pneumothorax on fertility status, even in the presence of pelvic endometriosis.

Inside the Endometrial Cell Signaling Subway: Mind the Gap(s)

Endometrial cells perceive and respond to their microenvironment forming the basis of endometrial homeostasis. Errors in endometrial cell signaling are responsible for a wide spectrum of endometrial pathologies ranging from infertility to cancer. Intensive research over the years has been decoding the sophisticated molecular means by which endometrial cells communicate to each other and with the embryo. The objective of this review is to provide the scientific community with the first overview of key endometrial cell signaling pathways operating throughout the menstrual cycle. On this basis, a comprehensive and critical assessment of the literature was performed to provide the tools for the authorship of this narrative review summarizing the pivotal components and signaling cascades operating during seven endometrial cell fate “routes”: proliferation, decidualization, implantation, migration, breakdown, regeneration, and angiogenesis. Albeit schematically presented as separate transit routes in a subway network and narrated in a distinct fashion, the majority of the time these routes overlap or occur simultaneously within endometrial cells. This review facilitates identification of novel trajectories of research in endometrial cellular communication and signaling. The meticulous study of endometrial signaling pathways potentiates both the discovery of novel therapeutic targets to tackle disease and vanguard fertility approaches.

The Prognostic Value of DNA Ploidy Determination in Endometrial Cancer

Aneuploidy, defined as an abnormal quantity of DNA in cells nuclei, is the most frequently observed genetic abnormality in cancer cells. Alterations in cell cycle control and chromosomal missegregation very often result in the accumulation of excess genetic material. These genetic reassortments simultaneously imbalance lots of structural and regulatory proteins. This chromosomal instability may be associated with mutations in tumor suppressor genes or loss of function of mismatch repair genes. These are common pathways of cancerogenesis in endometrial cancer. Endometrial cancer represents the most common female genital tract malignancy and is generally associated with favourable outcomes for affected patients. Despite this, recurrence rates and diseaserelated deaths are consistently reported in published series, also in so-defined low-risk groups of patients. Hence, is reasonable to believe that traditional prognostic factors–surgical stage, histologic type, tumor grading, myometrial deep of invasion, involvement of vascular spaces–do not definitely respond to the clinical needs of a comprehensive management. The determination of DNA ploidy in endometrial cancer has been widely investigated in the last decades and clear evidence is available of its direct correlation with prognosis. Despite this, poor acceptance and skepticism are common believes in the scientific community. Aim of the paper has been the attempt to underline, upon scientific strength, the importance and clinical potential usefulness of this determination in gynecological oncological practice.