Dermatofibrosarcoma Protuberans of the Vulva: A Review of the MITO Rare Cancer Group.

BACKGROUND: Vulvar dermatofibrosarcoma protuberans is an extremely rare disease. Its rarity can hamper the quality of treatment; deeper knowledge is necessary to plan appropriate management. The purpose of this review is to analyse the data reported in the literature to obtain evidence regarding appropriate disease management. METHODS: We made a systematic search of the literature, including the terms "dermatofibrosarcoma protuberans", "vulva", and "vulvar", alone or in combination. We selected articles published in English from two electronic databases, PubMed and MEDLINE, and we analysed their reference lists to include other potentially relevant studies. RESULTS: We selected 39 articles, with a total of 68 cases reported; they were retrospective case reports and case series. Dermatofibrosarcoma protuberans of the vulva tends towards local recurrence; an early and timely pathological diagnosis, together with an appropriate surgical approach, are of utmost importance to ensure free margins and maximise the curative potential. CONCLUSIONS: Even if this is an indolent disease and it generally shows a good prognosis, appropriate management may help in reducing the rate of local recurrences that may hamper patients' quality of life. Management by a multidisciplinary team is highly recommended.

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.

Menopause: a trigger for simultaneous development of ulcerative colitis in sigmoid neovagina and residual colorectum?

Vaginoplasty using sigmoid colon is a common technique used for the creation of a neovagina. However, the risk of adverse neovaginal bowel events is a common mentioned disadvantage. We report the case of a woman submitted to intestinal vaginoplasty for Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome at the age of 24 years who, with the onset of menopause, developed blood-stained vaginal discharge. Almost simultaneously, the patients complained chronic abdominal pain in lower left quadrant and prolonged diarrhea. General exams, Pap smear test, microbiological tests and viral test for HPV were negative. Neovaginal biopsies were suggestive for inflammatory bowel disease (IBD) of moderate activity and colonic biopsies were suggestive for ulcerative colitis (UC). The development of UC in the sigmoid neovagina and, almost simultaneously, in the remaining colon with onset of menopause raises important questions about etiology and pathogenesis of these diseases. Our case suggests that menopause may consider a trigger for the development of UC, due to the changes in the colon surface permeability related to menopause.

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.

A prospective, observational study of chemotherapy-induced ovarian damage on follicular reserve and maturation.

BACKGROUND: Chemotherapy negatively affects gonadal function, often resulting in premature ovarian failure (POF) due to ovarian reserve depletion. Mechanisms of gonadotoxicity, such as primordial follicle overactivation and "burnout", remain to be established. Ovarian tissue cryopreservation (OTC) before treatment plays an important role in safeguarding fertility. METHODS: This is a prospective observational study that aims to evaluate the feasibility of OTC after chemotherapeutic treatment initiation. Patients were divided into 2 groups depending on whether they received chemotherapy before the harvesting procedure (Group 1) or not (Group 2). The main outcomes of this study are serum anti-Mullerian hormone (AMH) levels and histological follicular counts on ovarian tissue biopsies. RESULTS: Between 2012 and 2020, 79 patients underwent OTC at our Hospital. Follicular counts from the ovarian biopsies of 30 post-pubertal patients and respective serum AMH levels were included in the analysis. AMH levels did not significantly differ between the 2 groups (P = 0.70) as well as the number of primordial follicles (P = 0.73). Ovarian biopsies of patients from Group 1 showed a higher number of primary follicles (P = 0.04) and atretic follicles (P = 0.05) with respect to Group 2. CONCLUSIONS: In conclusion, OTC appears to be feasible even after the start of chemotherapeutic treatment, since in treated patients, the main ovarian reserve indicators (number of primordial follicles and serum AMH levels) were not significantly reduced compared to untreated patients. The "burnout" theory of chemotherapeutic damage to the ovary seems to be supported by the higher number of primary follicles found in the ovaries of patients who received chemotherapy before OTC.

Locally Performed HRD Testing for Ovarian Cancer? Yes, We Can!

Assessment of HRD status is now essential for ovarian cancer patient management. A relevant percentage of high-grade serous carcinoma (HGSC) is characterized by HRD, which is caused by genetic alterations in the homologous recombination repair (HRR) pathway. Recent trials have shown that not only patients with pathogenic/likely pathogenic BRCA variants, but also BRCAwt/HRD patients, are sensitive to PARPis and platinum therapy. The most common HRD test is Myriad MyChoice CDx, but there is a pressing need to offer an alternative to outsourcing analysis, which typically requires high costs and lengthy turnaround times. In order to set up a complete in-house workflow for HRD testing, we analyzed a small cohort of HGSC patients using the CE-IVD AmoyDx HRD Focus Panel and compared our results with Myriad's. In addition, to further deepen the mechanisms behind HRD, we analyzed the study cohort by using both a custom NGS panel that analyzed 21 HRR-related genes and FISH analysis to determine the copy numbers of PTEN and EMSY. We found complete concordance in HRD status detected by the Amoy and the Myriad assays, supporting the feasibility of internal HRD testing.

Low-Malignant Schwannoma of the Cervix in Pregnancy: A Case Report and Literature Systematic Review.

Primary cervical melanocytic schwannomas, arising from the sympathetic chain, are very rare pigmented neural sheath tumors that, both grossly and clinically, are often misdiagnosed with other more frequent lesions of the uterine cervix. Literature review accounts for seventeen published cases of schwannomas of the cervix, ten of which are malignant and seven benign. Pathological examination with immunostaining techniques is essential for the correct diagnosis of these tumors. We report a case of primary cervical schwannoma in a 32-year-old female who was referred to our department at 13 weeks of gestation with a diagnosis of malignant melanoma of the cervix. Pathological review detailed a neoplasm with a myxoid spindle cell component and a minority of small epithelioid cells, with a low-malignant potential proliferation index: morphological and immunocytochemical findings were compatible with the diagnosis of nerve sheath tumor, type schwannoma. The patient underwent a vaginal trachelectomy and a prophylactic Shirodkar's cerclage. Pregnancy was carried on without any negative event. The patient delivered by a caesarean section a healthy female newborn. Placental histology was negative. After 6 years from the first diagnosis, the patient is healthy and disease free.

Surveillance alone in stage I malignant ovarian germ cell tumors: a MITO (Multicenter Italian Trials in Ovarian cancer) prospective observational study.

OBJECTIVE: The aim of this study was to analyze the oncological outcome of stage I malignant ovarian germ cell tumors patients included in the MITO-9 study to identify those who might be recommended routine surveillance alone after complete surgical staging. METHODS: MITO-9 was a prospective observational study analyzing data collected between January 2013 and December 2019. Three groups were identified: group A included 13 patients stage IA dysgerminoma and IAG1 immature teratoma; group B included 29 patients with stage IB-C dysgerminomas, IA-C G2-G3 immature teratomas and stage IA mixed malignant ovarian germ cell tumors and yolk sac tumors; and group C included five patients (two patients with stage IC1 and one patient with stage IC2 yolk sac tumors and two patients with mixed-stage IC2 malignant ovarian germ cell tumors). RESULTS: A total of 47 patients with stage I conservatively treated malignant ovarian germ cell tumors were analyzed. Two patients in group B were excluded from the routine surveillance alone group due to positive surgical restaging. Therefore, a total of 45 patients were included in the study. Median follow-up was 46.2 months (range; 6-83). In total, 14 of 45 patients (31.1%) received chemotherapy, while 31 (68.9%%) underwent surveillance alone. One patient in group A, with stage IA dysgerminoma had a relapse, successfully managed with conservative surgery and chemotherapy. None of the patients in group B and C relapsed. All patients were alive at completion of the study. Overall, among 31 patients (68.9%) who underwent surveillance alone, only one patient relapsed but was treated successfully. CONCLUSIONS: Our data showed that close surveillance alone could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C dysgerminomas, IA-IC G2-G3 immature teratomas, and IA mixed malignant ovarian germ cell tumors with yolk sac tumor component.

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.

Cervix neuroendocrine carcinoma presenting with severe hypokalemia and Cushing's syndrome.

Neuroendocrine carcinomas of the cervix are very rare, accounting for only 1-2% of all cervical cancers and <1% of all neuroendocrine tumors. Small-cell carcinoma of the cervix is associated with poor prognosis, even in early stages. Despite their neuroendocrine origin, tumors presenting with syndromes due to secreted neuroendocrine hormones are extremely rare. To date, only seven cases of cervical small-cell carcinoma associated with Cushing's syndrome due to ectopic ACTH secretion have been described. In most reports, Cushing's syndrome associated with these tumors occurred only in association with liver or lung metastasis. Only one single case of primary uterine cervix carcinoma secreting enough ACTH to induce Cushing's syndrome in the absence of metastatic disease has been described in 1994. Here, we describe a case of cervical small-cell carcinoma presenting with an acute onset of severe hypokalemia in Cushing's syndrome without metastatic disease to distant organs.

Malignant peritoneal mesothelioma in a woman with bilateral ovarian serous borderline tumour: Potential interactions between the two diseases.

We report a case of a 59-year-old woman with peritoneal malignant mesothelioma and no previous exposure to asbestos with a diagnosis of bilateral ovarian serous borderline tumour with peritoneal implants one year before. We discuss the histopathological and immunohistochemical findings to explain possible and potential interactions between the two diseases. To our knowledge, the association of both serous borderline ovarian tumour and malignant peritoneal mesothelioma has never been described before in the same woman and in such a tight temporal connection. This finding raises numerous issues about the origin of the two tumours and further biomolecular studies are needed to fully understand the carcinogenetic process. From a clinical point of view, this case report can be useful to gynaecologists because it leads to recommend a careful examination of the peritoneal cavity during a surgical resection of borderline serous tumour. Moreover, it may suggest performing a close follow-up associated with a careful surveillance of the patient, especially in the case of micropapillary pattern, to oncologists. A complete clinical approach could help to detect sooner possible relapses or other metachronous malignancies.

Fertility Preservation in Endometriosis Patients: Anti-Müllerian Hormone Is a Reliable Marker of the Ovarian Follicle Density.

OBJECTIVE: To analyze the ovarian reserve via measurement of follicular density and anti-Müllerian hormone (AMH) in endometriosis patients participating to a clinical program of cortical ovarian cryopreservation. DESIGN: Retrospective analysis of serum AMH levels and prospective investigation of ovarian follicle number. SETTING: University Hospital. PATIENTS: Two hundred and two women with endometriosis and 400 controls. INTERVENTIONS: Blood samples and ovarian biopsies. MAIN OUTCOME MEASURES: Correlation of serum AMH levels and the number of non-growing follicles in the biopsied cortical tissues in endometriosis and control subjects, including age, type of AMH kit, and the laboratory performing the analysis as covariates. RESULTS: AMH levels were shown to decrease with age in untreated endometriosis patients (P < 1.0 × 10-5) but they were significantly lower in endometriosis compared to controls only in patients over 36 years old (P = 2.7 × 10-4). The AMH decrease was faster in endometriosis compared to controls (beta = 0.27, P = 4.0 × 10-4). Primordial follicle number decreased with the reduction of AMH levels in both cases and controls (beta = 0.3; P = 0.04). CONCLUSION: AMH is a reliable marker of ovarian reserve in endometriosis patients, and it can predict follicular density in women undergoing ovarian tissue cryopreservation.

5-Hydroxytyrosol inhibits HIV-1 replication in primary cells of the lower and upper female reproductive tract.

We investigated the potential anti-HIV-1 activity of the candidate microbicide 5-hydroxytyrosol (5-HT) both in primary human cervical tissue explants (CTE), established from tissues of women undergoing histerectomy, and in endometrium-associated leukocytes (EAL). CTE were exposed to either the laboratory-adapted HIV-1BaL or to primary viral isolates in the presence or absence of 5-HT or 3TC/lamivudine as control and were then monitored for 12 days in terms of HIV-1 p24 Gag antigen production in culture supernatants. HIV-1BaL replication was also evaluated in EAL by reverse transcriptase (RT) activity. The highest nontoxic concentrations of 5-HT (200 and 100 µM for CTE and EAL, respectively) exerted a significant inhibitory effect on virus replication in both primary cell systems. 5-HT did not cause significant alterations of the activation profile of CD4+ and CD8+ T cells, in terms of CD4, CCR5, CD25, CD69 and HLA-DR expression, although it decreased the percentage of CD38+CD8+ T cells. Thus, 5-HT deserves consideration as a potential candidate microbicide for preventing HIV-1 transmission or curtailing its replication in the female reproductive tract.

Different Patterns of Disease Spread between Advanced-Stage Type I and II Epithelial Ovarian Cancer.

BACKGROUND AND AIMS: Two types of epithelial ovarian carcinoma (EOC) have been recently distinguished. Type I comprises low-grade serous, endometrioid and clear-cell tumors. High-grade endometrioid and serous tumors belong to type II. The aim of this study was to compare patterns of disease spread in advanced-stage type I and II EOCs at primary surgery. METHODS: Surgical and pathological data of 233 patients with advanced-stage EOCs were collected, 42 with type I and 191 with type II. The two groups were compared for tumor localization at primary surgery. Intraoperative mapping of ovarian cancer (IMO) was used to assess tumor dissemination. RESULTS: Tumor involvement was significantly higher in the type II group for the following: peritoneum (68.1 vs. 40.5%, p < 0.001), pouch of Douglas (60.2 vs. 40.5%, p = 0.06), vesicouterine ligament (40.8 vs. 19%, p = 0.027), diaphragm (45.0 vs. 11.9%, p < 0.001), serosa of liver (17.2 vs. 4.8%, p = 0.05), omentum (81.1 vs. 59.5%, p = 0.007), mesentery (42.9 vs. 16.7%, p = 0.005), pleural effusions (19.4 vs. 4.6%, p = 0.01) and ascites (60.7 vs. 21.4%, p < 0.001). IMO levels were different between the two groups (p = 0.001). CONCLUSIONS: This study provides clinical evidence in favor of the dualistic model of carcinogenesis, since types I and II are characterized by different findings at primary surgery.

Endometriosis-associated tumor at the inguinal site: report of a case diagnosed during pregnancy and literature review.

Malignant degeneration of endometriosis in the inguinal region is rare, and has only been reported in six cases in the literature, none of which was detected during pregnancy. We present the first case of endometriosis-associated adenocarcinoma in the inguinal region in a 34-year-old woman who was 35 weeks' pregnant. The tumor rapidly grew in the last 2 months of pregnancy as a left inguinal painful mass. Histologically, the tumor consisted of a moderate-to-poorly differentiated ovarian-type endometrioid adenocarcinoma arisen in endometriosis foci of both typical and atypical type. Elective labor induction was performed at 35 weeks of gestation and subsequently the patient underwent a conservative surgical treatment followed by chemotherapy. This case raises issues on the management of such an unusual tumor both during and outside pregnancy.

Characteristics of clear cell ovarian cancer arising from endometriosis: a two center cohort study.

OBJECTIVE: Endometrioid and clear cell ovarian tumors have been referred to as "endometriosis associated ovarian cancers". However, very few studies have compared clinical and prognostic features of endometriosis-associated cancers or cancers not associated with endometriosis according to specific histotypes. We have investigated clinical and histological features of the largest published series of clear cell ovarian cancers arising in endometriosis using a retrospective database. METHODS: Seventy three patients with a primary diagnosis of either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer have been divided into two groups according to the detection of cancer strictly arising from ovarian endometriosis or not (n=27 and n=46, respectively). Clinical and pathological data have been compared. RESULTS: Patients with clear cell carcinomas arising from endometriosis tend to be significantly younger (51.4±10.0 and 58.4±11.2years, p=0.02). FIGO stage, laterality, prevalence of pure versus mixed histology, and presence of synchronous endometrial carcinoma were not significantly different between the two groups. Unilateral ovarian involvement was more frequent in cases arising in endometriosis (85% vs 63%, p=0.04). Ascites was not found in any of the endometriosis-associated cancer cases vs 19.5% in patients without endometriosis. The presence of endometriosis did not affect 5-year overall survival rates. CONCLUSIONS: Endometriosis per se does not appear to be associated with a lower stage tumor or to predict prognosis in ovarian clear cell cancers. Unilateral involvement and reduced presence of ascites may be linked to the cystic nature of endometriosis which frequently presents as monolateral and in which associated tumors are more likely to be longer confined to the ovary before spreading.