Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer.

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.

Epithelial ovarian cancer is infiltrated by activated effector T cells co-expressing CD39, PD-1, TIM-3, CD137 and interacting with cancer cells and myeloid cells.

Introduction: Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity. Methods: In this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs). Results: Activated T cells showing features of partial exhaustion with a CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ signature. Conclusion: These data demonstrate that EOC is enriched in CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches.

Endometriosis-Related Ovarian Cancers: Evidence for a Dichotomy in the Histogenesis of the Two Associated Histotypes.

Evidence indicates that different pathways of malignant degeneration underlie the development of endometriosis-associated ovarian tumors of endometrioid and clear cell histotypes. The aim of this study was to compare data from patients affected by these two histotypes to investigate the hypothesis of a dichotomy in the histogenesis of these tumors. Clinical data and tumor characteristics of 48 patients who were diagnosed with either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer arising from endometriosis (ECC, n = 22) or endometriosis-associated endometrioid ovarian cancer (EAEOC, n = 26) were compared. A previous diagnosis of endometriosis was detected more frequently in the ECC group (32% vs. 4%, p = 0.01). The incidence of bilaterality was significantly higher in the EAOEC group (35% vs. 5%, p = 0.01) as well as a solid/cystic rate at gross pathology (57.7 ± 7.9% vs. 30.9 ± 7.5%, p = 0.02). Patients with ECC had a more advanced disease stage (41% vs. 15%; p = 0.04). A synchronous endometrial carcinoma was detected in 38% of EAEOC patients. A comparison of the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis showed a significantly decreasing trend for ECC compared to EAEOC (p = 0.02). These findings support the hypothesis that the origin, clinical behavior and relationship with endometriosis might be different for these histotypes. ECC, unlike EAEOC, seems to develop within an endometriotic cyst, thus representing a window of possibility for ultrasound-based early diagnosis.

Role of Machine Learning (ML)-Based Classification Using Conventional 18F-FDG PET Parameters in Predicting Postsurgical Features of Endometrial Cancer Aggressiveness.

PURPOSE: to investigate the preoperative role of ML-based classification using conventional 18F-FDG PET parameters and clinical data in predicting features of EC aggressiveness. METHODS: retrospective study, including 123 EC patients who underwent 18F-FDG PET (2009-2021) for preoperative staging. Maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were computed on the primary tumour. Age and BMI were collected. Histotype, myometrial invasion (MI), risk group, lymph-nodal involvement (LN), and p53 expression were retrieved from histology. The population was split into a train and a validation set (80-20%). The train set was used to select relevant parameters (Mann-Whitney U test; ROC analysis) and implement ML models, while the validation set was used to test prediction abilities. RESULTS: on the validation set, the best accuracies obtained with individual parameters and ML were: 61% (TLG) and 87% (ML) for MI; 71% (SUVmax) and 79% (ML) for risk groups; 72% (TLG) and 83% (ML) for LN; 45% (SUVmax; SUVmean) and 73% (ML) for p53 expression. CONCLUSIONS: ML-based classification using conventional 18F-FDG PET parameters and clinical data demonstrated ability to characterize the investigated features of EC aggressiveness, providing a non-invasive way to support preoperative stratification of EC patients.

Experimental drugs for fallopian cancer: promising agents in the clinical trials and key stumbling blocks for researchers.

INTRODUCTION: Fallopian tube carcinoma (FC) as a single entity is a rare disease. Although its diagnosis is increasing thanks to the widespread use of prophylactic salpingectomy, there are no clinical trials exclusively designed for FC. AREAS COVERED: This review aims at identifying the most promising trials and future therapeutic pathways in the setting of FC. EXPERT OPINION: Hot topics in FC treatment include the consequences of using PARP inhibitors (PARPi) as first-line therapy, ways to overcome platinum resistance, and the role of immunotherapy. Patient selection is a key point for future development of target therapies. Next-generation sequencing (NGS) is one of the most investigated technologies both for drug discovery and identification of reverse mutations, involved in resistance to PARPi and platinum. New, promising molecular targets are emerging. Notwithstanding the disappointing outcomes when used by itself, immunotherapy in FC treatment could still have a role in combination with other agents, exploiting synergistic effects at the molecular level. The development of cancer vaccines is currently hampered by the high variability of tumor neoantigens in FC. Genomic profiling could be a solution, allowing the synthesis of individualized vaccines.

Fertility sparing surgery in sex-cord stromal tumors: oncological and reproductive outcomes.

Sex cord stromal tumors are rare neoplasms, frequently diagnosed in young women often as early-stage disease. In patients who desire to preserve fertility, when possible, unilateral salpingo-oophorectomy with peritoneal surgical staging is a safe alternative to radical treatment. In this review, we analyze the available literature on the obstetrical outcomes after fertility-sparing surgery in a total of 255 patients with sex cord stromal tumors. We found that the spontaneous conception rate in granulosa cells tumor is encouraging (88.5%). In particular, juvenile granulosa cell tumors are associated with a more successful pregnancy rate than adult granulosa cells tumors (11/26 (42.3%) in juvenile granulosa cells tumors compared with 28.5% in adult granulosa cell tumors, respectively.) On the other hand, the results of obstetrical outcomes in Sertoli-Leydig cells tumors are less promising (7/36 (19.4%)). Unfortunately, no evidence on this topic is available for sex cord tumor with annular tubules due to the low incidence. Regarding the oncological outcomes of 900 cases of sex cord stromal tumors treated conservatively, data are reassuring with comparable outcomes between patients treated with conservative and radical surgery. Given the limited available data on this rare tumor, further studies are needed to evaluate the safety of conservative approaches and to define the obstetrical outcomes in this patient population.

Hybrid PET/MRI in Staging Endometrial Cancer: Diagnostic and Predictive Value in a Prospective Cohort.

AIM: The assessment of deep myometrial invasion (MI) and lymph node involvement is of utmost importance in the preoperative staging of endometrial cancer (EC). Imaging parameters derived respectively from MRI and PET have shown good predictive value. The main aim of the present study is to assess the diagnostic performance of hybrid 18F-FDG PET/MRI in EC staging, with particular focus on MI and lymphnodal involvement detection. PATIENTS AND METHODS: Prospective monocentric study including 35 patients with biopsy-proven EC undergoing preoperative 18F-FDG PET/MRI (December 2018-March 2021) for staging purpose. Histological examination was the reference standard. PET (SUVmax, SUVmean with a threshold of 40% of SUVmax-SUVmean40, metabolic tumor volume, total lesion glycolysis) and MRI (volume index [VI], total tumor volume, tumor volume ratio [TVR], mean apparent diffusion coefficient, minimum apparent diffusion coefficient) parameters were calculated on the primary tumor, and their role in predicting EC risk group, the presence of lymphovascular space invasion (LVSI), and MI was assessed. Receiver operating characteristics analysis was used to assess the predictive value of PET and MRI parameters on EC characteristics. RESULTS: Patients' median age was 66.57 years (SD, 10.21 years). 18F-FDG PET/MRI identified the primary tumor in all patients. Twenty-two of 35 patients had high-risk EC and 13/35 low-risk disease; 13/35 presented LVSI, 22/35 had deep MI at histological examination, and 13/35 had p53 hyperexpression.PET/MRI was able to detect lymphnodal involvement with high accuracy and high specificity (sensitivity of 0.8571, specificity of 0.9286, accuracy of 0.9143), also showing a high negative predictive value (NPV) for lymphnodal involvement (NPV of 0.9630, positive predictive value [PPV] of 0.7500).The assessment of deep MI using PET/MRI correctly staged 27 patients (77.1%; sensitivity of 0.7273, specificity of 0.8462, accuracy of 0.7714), with also a good PPV (PPV of 0.8889, NPV of 0.647).MRI-derived total tumor volume, VI, and TVR were significant in predicting EC groups (high-risk vs low-risk patients) (P = 0.0059, 0.0235, 0.0181, respectively). MRI-derived volume, VI, TVR, and PET-derived metabolic tumor volume and total lesion glycolysis were able to predict LVSI (P = 0.0023, 0.0068, 0.0068, 0.0027, 0.01394, respectively). Imaging was not able to predict grading, presence of deep MI, nor hyperexpression of p53. CONCLUSIONS: 18F-FDG PET/MRI has good accuracy in preoperative staging of EC; PET and MRI parameters have synergic role in preoperatively predicting LVSI, with MRI parameters being also predictive for EC risk group.

Impact of COVID-19 on medical treatment patterns in gynecologic oncology: a MITO group survey.

OBJECTIVE: COVID-19 is a global public health emergency. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological tumors. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) performed a survey to evaluate the impact of the COVID-19 pandemic on medical treatment of gynecological cancer, with a focus on chemotherapy and oral treatment with poly(ADP)-ribose polymerase inhibitors (PARP-i). METHODS: The survey consisted of a self-administered online questionnaire, sent via email between November 2020 and January 2021 to all members of MITO group. RESULTS: Forty-nine centers completed the questionnaire. The majority of respondents (83%) use screening tests to determine COVID-19 status in patients who were to undergo chemotherapy or oral medications. All respondents to our survey continued cancer therapy in patients who tested negative for COVID-19 during the pandemic. Seventy-three percent of respondents declared they stopped treatment with chemotherapy or PARP-i only after a positive swab and resumed therapy when negative tests were confirmed. CONCLUSIONS: COVID-19 positivity impacted patterns of treatment in patients diagnosed with ovarian cancer within the MITO group. Further investigations are needed to evaluate whether these modifications influence oncological clinical outcomes.

Stage I juvenile granulosa cell tumors of the ovary: A multicentre analysis from the MITO-9 study.

OBJECTIVE: Juvenile type granulosa cell tumor (JGCTs) are extremely rare, mainly diagnosed in young women and pre-pubertal girls at stage I disease. Literature is scanty and guidelines regarding the optimal management are still controversial. The aim of this study is to add on the experience of the MITO group (Multicenter Italian Trials in Ovarian Cancer). METHODS: Clinicopathological data from patients with stage I JGCTs were retrospectively collected. Descriptive statistics were used to characterize the patient population. Clinicopathological features and treatment variables were evaluated for association with relapse. RESULTS: Seventeen patients were identified. Surgical approach was laparoscopic and open for 7 (41%) and 10 (59%) patients, respectively. Fertility sparing surgery (FSS) was performed in 15 patients (88%): unilateral salpingo-oophorectomy (USO) in 11 patients, cystectomy with subsequent USO in 2 patients and cystectomy alone in the remaining 2. Adjuvant chemotherapy was given in 2 cases. After a median follow up time of 80 months, no recurrences were registered. CONCLUSIONS: Given the available data, minimally invasive surgery is safe in stage I JGCTs. Because of the good prognosis and of the young age of patients, FSS can be chosen in most of the cases. The role of cystectomy deserves further validation. The need of adjuvant chemotherapy in stage I disease is still unclear, even if available data does not seem to support treatment over surveillance.

Reproductive Outcomes and Fertility Preservation Strategies in Women with Malignant Ovarian Germ Cell Tumors after Fertility Sparing Surgery.

Malignant ovarian germ cell tumors are rare tumors that mainly affect patients of reproductive age. The aim of this study was to investigate the reproductive outcomes and fertility preservation strategies in malignant ovarian germ cell tumors after fertility-sparing surgery. Data in literature support that fertility-sparing surgery is associated with an excellent oncological outcome not only in early stages malignant ovarian germ cell tumors but also in advanced stages. Moreover, the possibility of performing conservative treatment should be considered even in case of relapse or advanced disease, given the high chemosensitivity. Indeed, available data have shown that menstrual function is maintained after platinum-based regimens in over 85-95% of patients with malignant ovarian germ cell tumors and rate of premature menopause reported in literature ranges between 3% and 7.4%, while premature ovarian failure rates are between 3.4% and 5%. Moreover, reproductive outcomes are about 80% with no increase in the risk of teratogenicity compared to general population. Therefore, conservative surgery for malignant ovarian germ cell tumors currently may represent a therapeutic option in patients who wish to preserve fertility but must be available for extended follow-up and after subscribing to informed consent.

Impact of COVID-19 in gynecologic oncology: a Nationwide Italian Survey of the SIGO and MITO groups.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has caused rapid and drastic changes in cancer management. The Italian Society of Gynecology and Obstetrics (SIGO), and the Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) promoted a national survey aiming to evaluate the impact of COVID-19 on clinical activity of gynecologist oncologists and to assess the implementation of containment measures against COVID-19 diffusion. METHODS: The survey consisted of a self-administered, anonymous, online questionnaire. The survey was sent via email to all the members of the SIGO, and MITO groups on April 7, 2020, and was closed on April 20, 2020. RESULTS: Overall, 604 participants completed the questionnaire with a response-rate of 70%. The results of this survey suggest that gynecologic oncology units had set a proactive approach to COVID-19 outbreak. Triage methods were adopted in order to minimize in-hospital diffusion of COVID-19. Only 38% of gynecologic surgeons were concerned about COVID-19 outbreak. Although 73% of the participants stated that COVID-19 has not significantly modified their everyday practice, 21% declared a decrease of the use of laparoscopy in favor of open surgery (19%). However, less than 50% of surgeons adopted specific protection against COVID-19. Additionally, responders suggested to delay cancer treatment (10%-15%), and to perform less radical surgical procedures (20%-25%) during COVID-19 pandemic. CONCLUSIONS: National guidelines should be implemented to further promote the safety of patients and health care providers. International cooperation is of paramount importance, as heavily affected nations can serve as an example to find out ways to safely preserve clinical activity during the COVID-19 outbreak.

Fertility preservation in women with cervical cancer.

Fertility preservation in women with cervical cancer is a demanding but evolving issue. Some remarkable achievements have been reached, in particular the improvement of primary and secondary prevention and the broadening of the indications for conservative surgery up to FIGO 2018 stage IB2. Natural pregnancy rate and the rate of obstetrics complications following conservative approach is satisfactory even if not optimal. On the other hand, the use of classic strategies for fertility preservation such as oocytes or ovarian cortex freezing is extremely limited, being the uterus compromised by treatment in a high proportion of cases. In fact, the availability of uterine surrogacy can play a role in the counseling and the decision-making process. The recent advent of uterus transplantation is fascinating but, at present, cannot be viewed as a realistic solution.

Synergic role of preoperative 18F-fluorodeoxyglucose PET and MRI parameters in predicting histopathological features of endometrial cancer.

BACKGROUND: The aim of the present study is to explore the correlation between PET and MRI parameters of primary tumour and clinicopathological features and to determine their synergic predictive role in patients with endometrial cancer candidate to surgery. METHODS: Retrospective study including 27 patients with endometrial cancer and preoperative 18F-fluorodeoxyglucose (18F-FDG)-PET and MRI scan. The following parameters, calculated on the primary tumour, were used for analysis: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) for PET scans; mean apparent diffusion coefficient (ADCmean) and volume index for MRI scans. FIGO stage, grade, histotype, lymphovascular space invasion (LVSI) and myometrial invasion were the considered clinicopathological features. RESULTS: MRI volume index was a good predictor for deep myometrial invasion [area under the curve (AUC) = 0.85; P = 0.003] and for LVSI (AUC = 0.74; P = 0.039). A cutoff value of 9.555 for MRI volume index was predictive for deep myometrial invasion (sensitivity = 84.6%; specificity = 76.9%); a cutoff of 12.165 was predictive for LVSI (sensitivity = 69.2%; specificity = 83.3%). A TLG cutoff value of 26.03 was predictive for deep myometrial invasion (sensitivity = 84.6%; specificity = 76.9%). A high-direct correlation was found with MRI volume index (rho = 0.722; P < 0.001); low-direct correlation with SUVmax (rho = 0.484; P = 0.012), SUVmean (rho = 0.47; P = 0.015) and TLG (rho = 0.482; P = 0.013) were identified. The SUVmax/ADCmean ratio showed a low-direct correlation with percentage of myometrial invasion (rho = 0.467; P = 0.016). CONCLUSION: Volume index, TLG and SUVmax/ADCmean ratio are associated with deep myometrial invasion. As myometrial invasion is the index used to predict lymph node involvement in endometrial cancer, the synergic use of these imaging parameters may be suggested to predict lymphnodal metastases.

Transvaginal ultrasound in evaluation and follow-up of ovarian granulosa cell tumors.

OBJECTIVE: Ultrasound features of granulosa cell tumors of the ovary are still poorly defined. The aim of this study is to widen current knowledge on the role of sonographic gray scale and pattern recognition in the characterization of these tumors and to compare the ultrasound characteristics of primary diagnosis and recurrences. METHODS: Transvaginal ultrasound images of primary diagnosis or recurrences of histologically-confirmed granulosa cell tumors of the ovary were retrospectively retrieved from a dedicated database designed for the collection of clinical and ultrasound data from January 2001 to January 2019. All patients included were treated at San Raffaele and Santa Chiara Hospitals. Women with a concomitant diagnosis of another malignancy other than endometrial carcinoma were excluded from the study. All ultrasound images were described according to International Ovarian Tumor Analysis terminology and examined by experienced ultrasound examiners. RESULTS: A total of 27 patients were included: 24 with adult and 3 with juvenile ovarian granulosa cell tumors. At primary diagnosis, mean ovarian mass size was 103.8 mm (range 30-200). On ultrasound evaluation at primary diagnosis, 12 patients presented with a multilocular solid lesion (48%), 9 with a solid lesion (36%), and 4 with a multilocular lesion(16%). The echogenicity of the cyst was low level or anechoic, mixed, or hemorrhagic in 56.3%, 31.2%, and 12.5% of cases, respectively. Most tumors (45.1%), including first diagnosis and relapses, had a moderate to high color score on doppler evaluation. CONCLUSIONS: Our study showed that sonographic features and pattern recognition of relapses were comparable to those of tumors at primary diagnosis. In order to highlight the importance of transvaginal ultrasound evaluation during follow-up, further studies based on a standardized ultrasound characterization of ovarian masses are recommended.

What women want: Fertility sparing surgery in Borderline ovarian tumours patients and pregnancy outcome.

OBJECTIVE: Borderline ovarian tumours (BOTs) are characterized by the presence of cellular proliferation and nuclear atypia without stromal invasion. Compared to malignant ovarian tumours, BOTs have better prognoses. The most important treatment of BOT is surgery. Considering the good prognosis of BOT, fertility-sparing surgery (FSS) can be considered for young women who desire to preserve fertility. Our study evaluated the pregnancy rate in patients with childbearing desire, the efficacy and risk of recurrence of women affected by BOTs who have undergone FSS. MATERIALS AND METHODS: Patients characteristics have been restrospectively retrieved for diagnosis made from June 2000 to December 2017 from San Raffaele Hospital and Policlinico Cagliari. Patients underwent FSS for BOT were interviewed about child wishing and pregnancy outcomes. RESULTS: 85 patients were recruited for the study. Median age at diagnosis was 33 years. Unilateral salpingo-oophorectomy was performed in 33 patients (38%), unilateral cystectomy in 40 (47%) and 12 underwent both procedures (14%). 40 women (50%) tried to conceive after surgery. The pregnancy rate was 73% and live birth rate was 67%. Childbearing desire and age at diagnosis were significantly associated with the pregnancy rate. CONCLUSIONS: Conservative surgical treatment seems to be a reasonable therapeutic option for women with BOTs who wish to preserve fertility. Our results suggest that the obstetric outcomes after FSS are promising. Maternal desire and the age of diagnosis are the most important factors affecting PR after surgery. Fertility counselling should be an integral part of the clinical management of women with BOT.

Management of recurrent ovarian cancer: when platinum-based regimens are not a therapeutic option.

Ovarian cancer relapses have been traditionally classified according to the platinum-free interval, leading to an arbitrary categorization of possible scenarios and treatment options. Its relevance in assessing treatment strategies has been revised in the last several years, as the panorama is constantly changing in the era of personalized medicine and targeted therapies. Factors to be considered while defining the best management of recurrent disease, and, consequently, the available treatment alternatives are increasing. Platinum remains one of the milestones of ovarian cancer treatment, but for some patients it might not be an ideal choice for several reasons other than limited platinum sensitivity. This review aims to analyze the scenarios in which platinum is not considered suitable in the management of patients with recurrent ovarian cancer, and the currently available alternatives.

Aggressive Surgical Approach for Treatment of Primary and Recurrent Retroperitoneal Soft Tissue Sarcoma.

To analyze treatment and survival in a series of resected patients with primary or recurrent retroperitoneal sarcoma (RPS) treated and prospectively followed at a single institution. Between July 1994 and December 2015, 89 patients (36 M, 53 F; mean age 60 years, range 25-79) were evaluated. For the purpose of analysis, complete resection was defined as removal of gross tumor with histologically confirmed clear resection margins. Eighty-three out of the 89 patients (93%), 46 of whom affected by primary RPS, and 37 by recurrent RPS, underwent surgical exploration. Sixty-two had a grossly and microscopically complete resection. Fifty-three out of 83 patients (64%) underwent removal of contiguous intra-abdominal organs. Preoperative mortality was nil and significant preoperative complications occurred in six cases only (7%). High-grade tumor pointed out to be a significant variable for a worse survival in all 83 patients amenable to undergo surgical resection (57% 5 years survival for low grade vs 14% for high grade; P = 0.0004). Among completely resected patients, only histologic grade clearly affected disease-free survival (72% 5 years survival for low grade vs 50% for high grade; P = 0.04), while the role of preoperative blood transfusions (67% 5 years survival for non-transfused patients vs 29% for transfused patients; P = 0.05) has to be evaluated in connection to patient complexity. Histological grade and recurrence are the most valuable prognostic predictors; in this clinical subset, an aggressive surgical approach in both primary and recurrent RPS is associated with a best long-term survival and disease-free survival.