A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms.

BACKGROUND: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival. RESULTS: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]). CONCLUSIONS: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).

CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer.

The CDKN1B gene, encoding for the CDK inhibitor p27kip1 , is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra-deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor-positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from premenopausal luminal breast cancer patients (n = 227, 4%) and in circulating cell-free DNA from metastatic luminal breast cancer patients (n = 59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation, leading to loss of most of the protein or of its C-terminal domain. Using a gene-editing approach in a luminal breast cancer cell line, MCF-7, we observed that the expression of p27kip1 truncating mutants that lose the C-terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knockout, indicating that the functions retained by the C-terminal portion are critical for its role as an oncosuppressor, at least in luminal breast cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Histological patterns and intra-tumor heterogeneity as prognostication tools in high grade serous ovarian cancers.

OBJECTIVE: High grade serous ovarian carcinoma (HGSOC) is the most common type of malignant ovarian neoplasm and the main cause of ovarian cancer related deaths worldwide. Although novel biomarkers such as homologous recombination deficiency testing have been implemented into the clinical decision-making algorithm since diagnosis, morphological classification and immunohistochemistry analysis are essential for diagnostic purpose. This study aims at identifying histologic and clinical features that can be predictive of patients' prognosis. METHODS: Morphological and architectural characterization including SET (Solid-Endometroid-Transitional)/Classic features was carried out in a cohort of 234 patients analyzing 695 slides. From each slide tumor infiltrating lymphocyte (TILs), the presence of necrosis, the number of mitoses, the presence of psammoma bodies, giant cells and atypical mitoses were recorded. Morphological heterogeneity was quantified by the Shannon's diversity index (SDI) considering the percentage of each architectural pattern per patient's slide. RESULTS: The frequency of architectural patterns and morphological variables varied with respect of the surgical strategy (primary debulking surgery vs interval surgery after neoadjuvant chemotherapy). HGSOCs exhibiting SET features had a longer overall as well as progression free survival. Among SET features, pseudo-endometrioid and transitional like patterns had the best outcome, while it was heterogenous for solid pattern, that had better outcome for BRCA 1 negative and less heterogeneous tumors. In patients submitted to neoadjuvant chemotherapy a higher intratumor heterogeneity as defined by SDI was a negative independent prognostic factor. CONCLUSIONS: A comprehensive histological examination considering architectural patterns and their heterogeneity can help in prognostication of HGSOCs.

Intestinal occlusion by gynecological cancers treated by percutaneous endoscopic gastrostomy and lanreotide: an Aviano National Cancer Institute experience.

The Commentary reports on our experience in Centro di Riferimento Oncologico IRCCS Aviano about the integrated and combined treatment with percutaneous endoscopic gastrostomy and lanreotide in patients with bowel obstructions by ovarian cancer and peritoneal carcinomatosis. We treated patients with gynecological cancers and bowel obstruction with percutaneous endoscopic gastrostomy and, when patients were partially responsive, with lanreotide. We registered a constant overall benefit for the quality of life and for the control of symptoms, which is very important especially during the home care follow-up of terminal patients.

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.

Cotyledonoid Leiomyoma Clinical Characteristics, Imaging Features, and Review of the Literature.

Cotyledonoid leiomyoma of the uterus is a rare variant of benign uterine leiomyoma. It has a favorable attitude, despite some ultrasound presentations. A bulky uterus with a heterogeneous mass with irregular margins, high vascularity, and infiltration of the myometrium can induce the suspicion of a malignant mesenchymal tumor and lead to a radical surgical treatment. If present, some imaging features may suggest this rare type of leiomyoma, thus avoiding extensive surgery, especially in young nulliparous women. We report 13 cases of cotyledonoid leiomyoma with clinical characteristics, imaging features, and a literature review.

A TGF-ß associated genetic score to define prognosis and platinum sensitivity in advanced epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is usually diagnosed at advanced stages with highly variable clinical outcomes, even among patients with similar clinical characteristics and treatments. Host immune system plays a pivotal role in EOC pathogenesis and progression. Here, we assessed the clinical significance of 192 single nucleotide polymorphisms (SNPs) on 34 immune-system related genes in EOC patients. METHODS: Two hundred and thirty advanced EOC patients treated with platinum-based chemotherapy were included. Germ-line DNA was analyzed with Illumina GoldenGate Genotyping Assay. RESULTS: Nineteen polymorphisms were significantly associated with overall survival (OS), 17 with progression free survival (PFS) and 20 with platinum-free interval (PFI). Of the 8 polymorphisms associated with all three outcomes, 7 SNPs belonged to genes involved in the TGF-ß pathway. A genetic score was built considering the unfavourable genotypes (UGs) of these 7 polymorphisms (group 0-2 UGs: presence of 0, 1, or 2 UGs; group 3-4 UGs: 3 or 4 UGs; group 5-7: 5, 6, or 7 UGs). According to this score, OS decreased as the number of UGs increased (median OS: 0-2 UGs = not reached, 3-4 UGs = 44.6 and 5-7 UGs = 19.3 months, p < 0.0001). The same trend was observed also for PFS (median PFS: 0-2 UGs = 21.5, 3-4 UGs = 17.3 and 5-7 UGs = 11 months, p < 0.0001) and PFI (median PFI: 0-2 UGs = 16.6, 3-4 UGs = 9.8 and 5-7 UGs = 3.8 months, p < 0.0001). The score was validated by permutation analysis. CONCLUSIONS: The proposed TGF-ß pathway score could be useful to define prognosis and platinum sensitivity of advanced EOC patients.

Human epidermal growth factor receptor-2 (HER2) is a potential therapeutic target in extramammary Paget's disease of the vulva.

BACKGROUND: Invasive vulvar Paget's disease with over-expression of the human epidermal growth factor receptor 2 (HER2) protein is potentially suitable for targeted therapy, especially in a metastatic setting where no effective treatments are available. METHODS: Four consecutive patients with HER2 positive advanced vulvar Paget's disease, treated with weekly trastuzumab (loading dose 4 mg/kg, then 2 mg/kg) and paclitaxel (80 mg/m2) followed by 3-weekly trastuzumab maintenance (6 mg/kg), are reported. RESULTS: Median age and follow-up of patients were 62.5 years (45-74) and 16 months (6-54), respectively. Complete or partial responses were observed in all patients. Median time to response was 3 months (range 2-4), while median duration of response was 10 months (range 2-34). Case 1 presented with pulmonary and lymph nodes involvement. She experienced a radiological complete response after 24 treatment administrations, and a progression-free survival of 36 months. At disease progression, treatment re-challenge achieved partial response. She is currently receiving treatment with trastuzumab-emtansine. Case 2 was a 74-year-old woman who developed pulmonary metastasis after first-line cisplatin treatment. She had a partial response and a progression-free survival of 10 months. Case 3 had inguinal and para-aortic lymphadenopathy in complete response after 18 treatment administrations. She developed brain metastasis while receiving trastuzumab maintenance. Case 4 was treated for locally advanced disease and experienced a subjective benefit with relief in perineal pain and itching. No unexpected treatment-related side effects were reported. CONCLUSIONS: Advanced vulvar Paget's disease is a rare disorder and no standard treatment is available. In the sub-group of HER2 positive disease, weekly paclitaxel-trastuzumab appears to be active and safe, and may be considered a therapeutic option in these patients.

Bevacizumab or PARP-Inhibitors Maintenance Therapy for Platinum-Sensitive Recurrent Ovarian Cancer: A Network Meta-Analysis.

INTRODUCTION: Targeted agents such as bevacizumab (BEV) or poly (ADP-ribose) polymerase inhibitors (PARPi) which have been added as concomitant or maintenance therapies have been shown to improve progression-free survival (PFS) in patients with platinum-sensitive recurrent ovarian cancer (PS rOC). In the absence of direct comparison, we performed a network meta-analysis considering BRCA genes status. METHODS: We searched PubMed, EMBASE, and MEDLINE for trials involving patients with PS rOC treated with BEV or PARPi. Different comparisons were performed for patients included in the PARPi trials, according to BRCA genes status as follows: all comers (AC) population, BRCA 1/2 mutated (BRCAm), and BRCA wild type patients (BRCAwt). RESULTS: In the overall population, PARPi prolonged PFS with respect to BEV (hazard ratio (HR) = 0.70, 95% CI 0.54-0.91). In the BRCA mutated carriers, the PFS improvement in favor of PARPi appeared to be higher (HR = 0.46, 95% CI 0.36-0.59) while in BRCAwt patients the superiority of PARPi over BEV failed to reach a statistically significance level (HR = 0.87, 95% CI 0.63-1.20); however, according to the SUCRA analysis, PARPi had the highest probability of being ranked as the most effective therapy (90% and 60%, for PARPi and BEV, respectively). CONCLUSIONS: PARPi performed better as compared with BEV in terms of PFS for the treatment of PS rOC, especially in BRCAm patients who had not previously received PARPi.

Number of Nodes Removed With Inguinofemoral Lymphadenectomy and Risk of Isolated Groin Recurrence in Women With FIGO Stage IB-II Squamous Cell Vulvar Cancer.

AIM: The aim of this study was to evaluate if the lymph node count from inguinofemoral lymphadenectomy impacted the risk of isolated groin recurrence in patients with node-negative squamous cell vulvar cancer. MATERIALS AND METHODS: This is a retrospective cohort study of women with squamous cell vulvar cancer (stage IB-II according to the 2009 Revised International Federation of Gynecology and Obstetrics staging system) who underwent primary radical vulvar surgery and groin lymphadenectomy between January 2005 and December 2014. Patients' sociodemographic characteristics, the disease characteristics, the number of nodes removed from each groin, and the oncologic outcome were evaluated. A cutoff value of at least 6 nodes removed from each groin was used to define the adequacy of inguinofemoral dissection. RESULTS: Seventy-six patients, fulfilling the study inclusion criteria, were considered. The mean number of nodes removed (bilaterally) was 14.5 (±5.3, SD), with a range of 2 to 29 nodes. Thirty-three women (43.4%) had less than 6 nodes removed from each groin. In the whole study cohort, 4 cases of isolated groin recurrence (5.3%) were detected, and all these recurrences developed in patients with less than 6 nodes removed. Considering the demographic, clinical, and histopathological characteristics potentially related to the risk of groin recurrence, only the number of nodes removed showed a significant correlation. CONCLUSIONS: Women treated for vulvar cancer in which less than 6 nodes are removed from each groin are at higher risk of groin recurrence.

Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS).

Somatic mutations in TP53 are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including TP53, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel TP53 somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: TP53 c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); TP53 c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); TP53 c.826_827GC>AT (p.Ala276Ile, missense); TP53 c.1022insT (p.Arg342Profs*5, frameshift INDEL); TP53 c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and TP53 c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel TP53 variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported TP53 somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.

Cytoreduction (Peritonectomy Procedures) Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Advanced Ovarian Cancer: Retrospective Italian Multicenter Observational Study of 511 Cases.

PURPOSE: The aim of this study was to help with the process of selecting patients with advanced ovarian cancer to undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) by analyzing outcome data at distinct clinical time points reflecting the natural history of the disease. METHODS: In a retrospective Italian multicenter study investigating patients with advanced ovarian cancer who underwent CRS plus HIPEC between 1998 and 2014, we analyzed data for consecutive patients at eight treatment time points: primary debulking surgery (PDS); interval debulking surgery after partial response, after no response, and after a pathologic complete response to neoadjuvant chemotherapy; first recurrence with a progression-free interval >12, <12 months, or >12 months in patients who underwent further chemotherapy before CRS and HIPEC; and patients who underwent two or more CRS procedures and chemotherapy lines before CRS and HIPEC. RESULTS: The 511 enrolled patients underwent 3373 procedures; 72.6% achieved complete cytoreduction, with an overall major morbidity of 17.4%. At a median follow-up of 53.8 months, overall survival (OS) was 54.2 months (95% confidence interval [CI] 44-58.4) and progression-free (PFS) survival was 16.6 months (95% CI 14.7-19.1). Outcome analysis in patients in whom CRS plus HIPEC was used for primary advanced cancer or recurrent ovarian cancer showed significant differences in OS and PFS according to the time points analyzed. Multivariate analysis identified completeness of CRS, Peritoneal Cancer Index, and the times when patients underwent CRS plus HIPEC as independent prognostic factors. CONCLUSIONS: This selective information on survival should help in interpreting the findings from ongoing randomized studies focusing on CRS plus HIPEC in patients with advanced ovarian cancer.

Laser Excisional Treatment for Vaginal Intraepithelial Neoplasia to Exclude Invasion: What Is the Risk of Complications?

OBJECTIVE: We undertook a retrospective analysis of the incidence of complications of carbon dioxide (CO2) laser excision for high-grade vaginal intraepithelial neoplasia (HG-VaIN). MATERIALS AND METHODS: Retrospective large case series on 128 CO2 laser excisions for HG-VaIN in 106 women treated at the Department of Gynecologic Oncology, Oncologic Referral Center, Aviano, Italy. These procedures were performed under local anesthesia with a 20-W continuous laser beam focused to a 0.2-mm spot size. Complications were defined as "minor" when limited to vagina, and "major" when surrounding organs were injured or the vaginal vault was opened.To identify possible factors associated with surgical complications, we performed a univariate analysis with the t test for continuous variables and χ or Fisher exact test for qualitative variables as appropriate. RESULTS: The overall rate of complication was 7.8% (10/128); nine of them were vaginal bleeding, and only one (0.8%) was a major complication with vaginal vault perforation.A greater number of previous destructive treatments and of two or more previous laser vaginal excisional treatments was present in patients with complications compared with ones without complications (10% vs 3.9 %, p = .92, and 30% vs 15.2%, p = .44, respectively), although these differences were not statistically significant. A total of 10.5% (6/57) of occult vaginal cancer was detected in women with initial diagnosis of VaIN3 (HG-VaIN) on biopsy. CONCLUSIONS: Carbon dioxide laser excision for HG-VaIN seems to be a safe approach with low rate of complications, probably because of the better accuracy achieved by CO2 laser resections, and permits diagnosis of occult invasive disease.

Primary surgical cytoreduction in advanced ovarian cancer: An outcome analysis within the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group.

OBJECTIVE: To draw a reliable picture of the surgical management of advanced ovarian cancer (AOC) within the MITO Group, trying to correlate the disease extent at presentation, the category of center, and surgical outcome. METHODS: Three tertiary referral centers for gynecologic oncology and four non-oncologic referral gynecologic surgical centers, participated in the project. A questionnaire was adopted to register perioperative data on AOCs (FIGO Stage IIICIV) consecutively operated on for a period of 12months. RESULTS: A total of 205 patients were registered into the study: 140 and 65 were recruited in oncological referral centers and non-referral centers, respectively. Following a multivariate analysis, the Eisenkop score and the category of center resulted the most potent predictors of complete surgical cytoreduction followed by PCI, preoperative CA125, and ASA score. Complete surgical cytoreduction was associated with oncological referral centers (60% vs 24.6%, p<0.001). The proportion of patients undergoing additional surgical procedures was significantly different comparing the two categories of centers (at least one additional procedure was performed in 81.4% vs 50.8% in oncological referral centers compared to the others, p<0.001). Despite the more aggressive surgery performed in oncological referral centers, the perioperative outcome measures were not significantly different in the two groups. CONCLUSIONS: The chance of obtaining a complete cytoreduction mainly depends on patient characteristics, tumor spread, and quality of treatment. The latter is amenable for direct influence, and therefore, seems to be of utmost importance when considering efforts aiming at improvement in the outcome of this disease.

Decompressive percutaneous endoscopic gastrostomy in advanced cancer patients with small-bowel obstruction is feasible and effective: a large prospective study.

PURPOSE: The purpose of this study was to evaluate patient-centered outcomes of decompressive percutaneous endoscopic gastrostomy (dPEG) in patients with malignant bowel obstruction due to advanced gynecological and gastroenteric malignancies. METHODS: This is a prospective analysis of 158 consecutive patients with small-bowel obstruction from advanced gynecological and gastroenteric cancer who underwent PEG or percutaneous endoscopic jejunostomy (PEJ) positioning for decompressive purposes from 2002 to 2012. All of them had previous abdominal surgery and were unfit for any other surgical procedures. Symptom relief, procedural complications, and post dPEG palliation were assessed. Global Quality of Life (QoL) was evaluated in the last 2 years (25 consecutive patients) before and 7 days after dPEG placement using the Symptom Distress Scale (SDS). RESULTS: dPEG was successfully performed in 142 out of 158 patients (89.8 %). Failure of tube placement occurred in 16 patients (10.1 %). In 8/142 (5.6 %) patients, dPEG was guided by abdominal ultrasound. In 3/142 patients, dPEG was CT-guided. In 14 (9.8 %) patients, who had previously undergone total or subtotal gastrectomy, decompressive percutaneous endoscopic jejunostomy (dPEJ) was performed. In 1/14 patients, dPEJ was CT-guided. Out of 142 patients, 110 (77.4 %) experienced relief from nausea and vomiting 2 days after PEG. Out of 142 patients, 116 (81.6 %) were discharged. The median postoperative hospital stay was 9 days (range 3-60). Peristomal infection (14 %) and intermittent obstruction (8.4 %) were the most frequent complications associated with PEG. Median survival time was 57 days (range 4-472) after PEG placement. Twenty-five patients had QoL properly evaluated with SDS score before and 7 days after dPEG. Sixteen patients (64 %) out of 25 exhibited an improvement of QoL (p < 0.05), 7 (28 %) patients exhibited a non-significant worsening of QoL (p = 0.18), and in 2 (8 %) patients, it remained unmodified. CONCLUSIONS: dPEG is feasible, effective, relieves nausea and vomiting in patients with unremitting small-bowel obstruction from advanced gynecological and gastroenteric cancer, and improves QoL.

Surgical Treatment of Paget Disease of the Vulva: Prognostic Significance of Stromal Invasion and Surgical Margin Status.

OBJECTIVE: The aim of the study was to evaluate the risk of recurrence according to the surgical margin status and the presence of invasion or of superficially invasive carcinoma in patients with extramammary Paget disease (EMPD) of the vulva, who underwent elective surgical treatment. MATERIALS AND METHODS: We performed a retrospective analysis of 27 patients with first diagnosis of extramammary Paget disease of the vulva, who underwent primary and elective surgical treatment from January 1989 to December 2014. A p value of less than .05 was considered statistically significant. Multivariable logistic regression was performed to adjust for confounding factors. RESULTS: We observed invasive disease in 11 cases, with microinvasion in 8 of them. A positive surgical margin was found in 10 patients. During a median follow-up period of 79.5 months, 8 patients (29.6%) showed a first recurrence after a median (range) time of 4.9 (2.3-7.1) years. No significant differences were observed between patients with recurrence and patients without recurrence with respect to age, number of vulvar sectors involved, bilaterality and multifocality, presence of invasion or microinvasion, and surgical margin status. However, during the follow-up period, the presence of invasion was higher (67% vs 41%) in patients with recurrence compared with patients without recurrence. CONCLUSIONS: The rate of recurrence of the disease after therapy is high. Patients should be subjected to a close and long-term follow-up to identify those who must undergo further treatment, especially if they presented with an invasive or even microinvasive disease. A free margin of no greater than 1 to 2 cm might be the most appropriate surgical choice.

Vaginal Intraepithelial Neoplasia: Histopathological Upgrading of Lesions and Evidence of Occult Vaginal Cancer.

OBJECTIVE: The aim of this study was to analyze women treated with excisional procedures for vaginal high-grade squamous intraepithelial lesions (HSILs). The histopathological upgrading of the lesions previously detected on vaginal biopsy and the presence of occult invasive vaginal cancer in the specimens excised were investigated, to identify a higher risk subset of women. MATERIALS AND METHODS: A retrospective analysis of the medical records of 86 women with a biopsy histopathologic diagnosis of vaginal HSIL (vaginal intraepithelial neoplasias [VaINs]: VaIN2 and VaIN3) and subsequent excisional therapy, consecutively referred to the Aviano National Cancer Institute (Aviano, Italy) from January 1991 to April 2014, was performed. RESULTS: Of the 86 patients, 4 cases (4.6%) of occult vaginal cancer were detected, all of them in women previously diagnosed with VaIN3 on biopsy (4/39 cases, 10.3%). Women with diagnosis of VaIN2 on biopsy showed an upgrading of lesions, with diagnosis of VaIN3 on the final specimen in 5 (10.6%) of 47 cases, with no cases of VAIN2 upgraded to invasive cancer. In 33.3% of the women initially diagnosed with VaIN2 and with previous hysterectomy for human papillomavirus-related disease, a final histopathological upgrading of lesions emerged. Furthermore, tobacco use was significantly related to the histopathological upgrading of lesions previously detected on vaginal biopsy. CONCLUSIONS: Women diagnosed with VaIN3 should be treated with excisional procedures as first-line surgical approach, given the risk of occult invasive disease in 10% of the cases. Women diagnosed with VaIN2 and with previous hysterectomy for human papillomavirus-related cervical diseases should always be carefully evaluated and possibly excised, given the higher risk of histopathological upgrading of lesions and thus the potential risk of occult vaginal cancer. Tobacco users should be considered as high-risk group.

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.

Conversion in endometrial cancer patients scheduled for laparoscopic staging: a large multicenter analysis: conversions and endometrial cancer.

BACKGROUND: Data on patients with endometrial cancer converted to laparotomy are totally lacking. The aim of the present study was to evaluate surgical and oncological outcomes in patients with endometrial cancer scheduled for laparoscopic staging but converted to laparotomy. METHODS: Data of consecutive patients who had undergone surgery for staging endometrial cancer in seven Italian centers were reviewed. Patients' characteristics and surgical and oncological data were noted and analyzed according to surgery, i.e. laparotomy, laparoscopy, and laparoscopy converted to laparotomy. RESULTS: Seventy-one out of 512 (13.9 %) patients scheduled to laparoscopy were converted to laparotomy for reasons related to anesthesiology [38/71 (53.5 %)] or surgery [33/71 (46.5 %)]. The conversion rate varied among stages [41/460 (8.9 %), 13/27 (48.1 %), 17/25 (68.0 %) in patients with stage I, II, and endometrial cancers, respectively]. Significant (P < 0.05) differences among groups were detected in patients' age, body mass index and previous pelvic surgery, and in the distribution of stages and histotype of endometrial cancers. The Kaplan-Meier procedure showed that the cumulative probability of first recurrence (P = 0.089, 0.590 and 0.084 for stage I, II and III, respectively) and of death (P = 0.108, 0.567 and 0.372 for stage I, II and III, respectively) categorized by stages did not attain statistical significance by log-rank testing after correction for confounding factors. CONCLUSIONS: The surgical and oncological outcomes of converted patients are no different from those of patients staged successfully with laparoscopy or with laparotomy. The conversion to laparotomy should be not considered per se a complication.

Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.

Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.