Uterine serous carcinoma: role of surgery, risk factors and oncologic outcomes. Experience of a tertiary center.

OBJECTIVE: To evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC). METHODS: Data of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: Records of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7-117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5-44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1-56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery. CONCLUSIONS: In apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.

Sentinel node mapping vs. sentinel node mapping plus back-up lymphadenectomy in high-risk endometrial cancer patients: Results from a multi-institutional study.

OBJECTIVE: Sentinel node mapping (SLN) has replaced lymphadenectomy for staging surgery in apparent early-stage low and intermediate risk endometrial cancer (EC). Only limited data about the adoption of SNM in high risk EC is still available. Here, we evaluate the outcomes of high-risk EC undergoing SNM (with or without back-up lymphadenectomy). METHODS: This is a multi-institutional international retrospective study, evaluating data of high-risk (FIGO grade 3 endometrioid EC with myometrial invasion >50% and non-endometrioid histology) EC patients undergoing SNM followed by back-up lymphadenectomy and SNM alone. RESULTS: Chart of consecutive 196 patients were evaluated. The study population included 83 and 113 patients with endometrioid and non-endometrioid EC, respectively. SNM alone and SNM followed by back-up lymphadenectomy were performed in 50 and 146 patients, respectively. Among patients having SNM alone, 14 (28%) were diagnosed with nodal disease. In the group of patients undergoing SNM plus back-up lymphadenectomy 34 (23.2%) were diagnosed with nodal disease via SNM. Back-up lymphadenectomy identified 2 (1%) additional patients with nodal disease (in the para-aortic area). Back-up lymphadenectomy allowed to remove adjunctive positive nodes in 16 (11%) patients. After the adoption of propensity-matched algorithm, we observed that patients undergoing SNM plus back-up lymphadenectomy experienced similar disease-free survival (p = 0.416, log-rank test) and overall survival (p = 0.940, log-rank test) than patients undergoing SLN alone. CONCLUSIONS: Although the small sample size, and the retrospective study design this study highlighted that type of nodal assessment did not impact survival outcomes in high-risk EC. Theoretically, back-up lymphadenectomy would be useful in improving the removal of positive nodes, but its therapeutic value remains controversial. Further prospective evidence is needed.

High-risk HPV-positive and -negative high-grade cervical dysplasia: Analysis of 5-year outcomes.

OBJECTIVE: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia. METHODS: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes. RESULTS: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test). CONCLUSIONS: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.

Spotlight on the role of human papillomavirus vaccines.

In high income setting, the massive implementation of screening programs has reduced the incidence of cervical cancer, dramatically. However, cervical cancer still remains a major health concern, being one of the most common cause of death for cancer among women. The adoption of primary prevention through vaccination against HPV aims to reduce the prevalence of HPV-related lesions and cervical cancer. Accumulating data highlighted the cost-effectiveness of introducing HPV vaccination for adolescent and young adults. In the present review, we critically evaluated the role of vaccination against HPV, focusing much more on the role of vaccination in specific cluster of subjects (eg, post-treatment and older adults). Additionally, we evaluated the available evidence on the role of vaccination in HIV-positive subjects and in women receiving solid organs transplantation. We observed that although vaccination might be considered effective in those cluster of subjects; further evidence is needed to assess the cost-effectiveness of vaccination in these settings.

Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison.

Background: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. Methods: This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% (n = 2) and 5.7% (n = 102) after conization plus vaccination and conization alone, respectively (p = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively (p = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia; p = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia; p = 0.031). Conclusions: Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.

The impact of HPV-specific infection in women diagnosed with atypical glandular cells: Results from the HPV-AGC study.

OBJECTIVE: To evaluate the impact of various HPV types on the risk of developing lesions of the uterus (either uterine cervix and endometrium) in women diagnosed with "atypical glandular cells" (AGC) at Pap smear. METHODS: This is a multi-institutional retrospective study. Data of women diagnosed with AGC were retrospectively reviewed. All patients included had data about HPV DNA testing and 1-year clinical follow-up. RESULTS: Overall, chart of 480 patients were evaluated. After the exclusion of 286 patients, data of 194 patients were available for the analysis. Mean age was 43.9 (±6.0) years. HPV infection was documented in 136 women (70.1 %). Among HPV positive patients the risk of having/developing a lesion was 33.8 % (n = 46). Lesions included low- (L-SIL) and high- (H-SIL) squamous intraepithelial lesions, in situ adenocarcinoma of the uterine cervix, invasive cancer of the uterine cervix, endometrial hyperplasia and endometrial cancer in 16 (11.7 %), 18 (13.2 %), 6 (4.4 %), 3 (2.2 %), 2 (1.5 %) and 1 (1%), respectively. Among HPV negative patients the risk of having/developing a lesion was 15.5 %. They included l-SIL, H-SIL, in situ adenocarcinoma, endometrial hyperplasia and endometrial cancer in 1 (1.7 %), 1 (1.7 %), 1 (1.7 %), 3 (5.1 %) and 3 (5.1 %), respectively. Patients diagnosed with HPV16 were at higher risk of having/developing cervical lesions in comparison to patients with other HPV infections (p < 0.01). In comparison to other HPV types, the presence of HPV 18, 31, 33, and 45 did not increase the risk of developing a lesion over the time (p > 0.2). HPV positive patients were at higher risk of being diagnosed with a cervical lesion within 6 months from detection of AGC. CONCLUSIONS: Patients diagnosed with AGC are at risk to have / developing cervical and uterine lesions. Further prospective evidence is needed.

Recurrence rate after loop electrosurgical excision procedure (LEEP) and laser Conization: A 5-year follow-up study.

OBJECTIVE: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+). METHODS: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. RESULTS: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001). CONCLUSIONS: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia.

The role of sentinel lymph node mapping in lower genital tract melanoma.

INTRODUCTION: Vulvar and vaginal melanomas are rare cancers of the female genital tract and account for 1% to 3% of all melanomas diagnosed in women. Due to the rarity of the disease, few data are available on the clinical and pathologic features of these cancers. Furthermore, treatment options are generally based on extrapolations of the information available for the more common cutaneous counterparts. Surgery represents the mainstay of treatment for lower genital tract melanoma. Moreover, the role of sentinel lymph node (SLN) assessment is controversial because no prospective data are available. EVIDENCE ACQUISITION: Data were collected from Medline, Embase, Web of Sciences and Scopus databases. On July 10, 2020, we used the search comprising the terms "vulvar melanoma," "genital melanoma" and "vulvovaginal melanoma" including only studies in which SLN biopsy was performed. EVIDENCE SYNTHESIS: Ten retrospective studies have been found. No randomized trials have been reported. The studies included 132 patients while only 63 (47%) undergone SLN. 99mTC with or without blue dye followed by ultrastaging was highly accurate and is currently the gold standard. Mean detection rate was 98.3%. No clear evidence supported the execution of back lymphadenectomy (after SLN mapping), in fact, extrapolating data from cutaneous melanomas of other sites, completion of lymphadenectomy does not confer a melanoma-specific survival advantage. CONCLUSIONS: Although the small amount of available data, sentinel lymph node procedure is feasible and capable of identifying patients who have occult lymph node metastases. However, the potential role of the sentinel lymph node procedure as an alternative method of lymph node staging in patients with vulvar or vaginal melanoma needs further investigation.

Management of patients with ovarian cancer in the COVID-19 era.

At the beginning of 2020, coronavirus disease 2019 (COVID-19) spreads worldwide. Patients with ovarian cancer should be considered at high-risk of developing severe morbidity related to COVID-19. Most of them are diagnosed in advanced stages of disease, and they are fragile. Here, we evaluated the major impact of COVID-19 on patients with ovarian cancer, discussing the effect of the outbreak on medical and surgical treatment.

Immunotherapy for platinum-resistant ovarian cancer.

Ovarian cancer is characterized by a high mortality on incidence ratio. Although the majority of patients achieve complete response after primary treatment, approximately 65-80% of patients recur with the first 5 years. Platinum-free interval is one of the main prognostic factors. Patients recurring with 6 months within the end of platinum-based chemotherapy are characterized by poor prognosis. To date no effective treatment modality are identified for those patients. The mainstay of treatment for platinum-resistant ovarian cancer is single agent chemotherapy. Other treatment modalities have tested in this setting with discouraging results. Growing evidence suggested that immunotherapy would improve outcomes of patients with various types of solid tumors including melanoma, non-small cell lung cancer as well as uterine malignancies. Here, we reviewed current evidence on the adoption of immunotherapy in platinum-resistant ovarian cancer. To date no mature evidence supports the routine adoption of immunotherapy in ovarian cancer patients. Further strategies have to be explored.

Cancer patients affected by COVID-19: Experience from Milan, Lombardy.

OBJECTIVE: SARS-CoV-2 pandemic is continuing to spread. There are growing concerns on the impact of COVID-19 in cancer patients. Several papers reporting recommendations and guidelines are published. But few data on cancer patients affected by COVID-19 are available. METHODS: This is a retrospective study including all consecutive patients affected by gynecological cancer who developed COVID-19. All patients were treated in an academic setting (in Milan, Lombardy, Italy) between February and March 2020. RESULTS: Overall, 355 patients had active treatment during the study period due to newly diagnosed or recurrent gynecological disease. Among those, 19 (5.3%) patients affected developed COVID-19. All patients were asymptomatic at the time of COVID-19 detection. Six patients were diagnosed before starting planned treatments; while the remaining 13 were diagnosed for COVID-19 after their started their treatments. Considering the first group of six patients, one patient died due to COVID-19 3 days after the diagnosis; while the other patients recovered from COVID-19 after a median of three weeks. The latter group of 13 patients (treatments started) included five patients who underwent surgery and eight patients who underwent chemotherapy. Focusing on five patients who were diagnosed after surgery, we observed that two patients died during postoperative course, while in other two cases prolonged hospitalization was needed. One patient had no issues. Chemotherapy was delayed for the remaining patents without sequelae. CONCLUSIONS: Our report highlights that COVID-19 impacts the quality of treatments for cancer patients. Mortality rate is high, especially after surgery. More important, patients under active treatment for cancer are at high risk of developing severe evolution of COVID-19. Prioritizing patients journey during COVID-19 is of paramount importance.

Gynecologic oncology at the time of COVID-19 outbreak.

The World Health Organization (WHO) classified the novel coronavirus (i.e., coronavirus disease 2019 [COVID-19]) as a global public health emergency. COVID-19 threatens to curtail patient access to evidence-based treatment. Medicine is changing, basically due to the limited available resources. In the field of gynecologic oncology, we have to re-design our treatments' paradigm. During COVID-19 pandemic outbreak, the highest priority is to achieve the maximum benefit from less demanding procedures. Extensive procedures should be avoided, in order to reduce hospitalization and postoperative events that might increase the in-hospital spread of the virus. There are ongoing concerns on the use of laparoscopic procedures, related to the possible contamination of the staff working in the operation room. Other minimally invasive techniques, including, vaginal surgery as well as robotic-assisted and isobaric procedures would be preferred over laparoscopy. A fair allocation of resources is paramount adequate treatments.