R. Fruscio

Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group

Objectives To prospectively assess the diagnostic performance of simple ultrasound rules to predict benignity/malignancy in an adnexal mass and to test the performance of the risk of malignancy index, two logistic regression models, and subjective assessment of ultrasonic findings by an experienced ultrasound examiner in adnexal masses for which the simple rules yield an inconclusive result. Design Prospective temporal and external validation of simple ultrasound rules to distinguish benign from malignant adnexal masses. The rules comprised five ultrasonic features (including shape, size, solidity, and results of colour Doppler examination) to predict a malignant tumour (M features) and five to predict a benign tumour (B features). If one or more M features were present in the absence of a B feature, the mass was classified as malignant. If one or more B features were present in the absence of an M feature, it was classified as benign. If both M features and B features were present, or if none of the features was present, the simple rules were inconclusive. Setting 19 ultrasound centres in eight countries. Participants 1938 women with an adnexal mass examined with ultrasound by the principal investigator at each centre with a standardised research protocol. Reference standard Histological classification of the excised adnexal mass as benign or malignant. Main outcome measures Diagnostic sensitivity and specificity. Results Of the 1938 patients with an adnexal mass, 1396 (72%) had benign tumours, 373 (19.2%) had primary invasive tumours, 111 (5.7%) had borderline malignant tumours, and 58 (3%) had metastatic tumours in the ovary. The simple rules yielded a conclusive result in 1501 (77%) masses, for which they resulted in a sensitivity of 92% (95% confidence interval 89% to 94%) and a specificity of 96% (94% to 97%). The corresponding sensitivity and specificity of subjective assessment were 91% (88% to 94%) and 96% (94% to 97%). In the 357 masses for which the simple rules yielded an inconclusive result and with available results of CA-125 measurements, the sensitivities were 89% (83% to 93%) for subjective assessment, 50% (42% to 58%) for the risk of malignancy index, 89% (83% to 93%) for logistic regression model 1, and 82% (75% to 87%) for logistic regression model 2; the corresponding specificities were 78% (72% to 83%), 84% (78% to 88%), 44% (38% to 51%), and 48% (42% to 55%). Use of the simple rules as a triage test and subjective assessment for those masses for which the simple rules yielded an inconclusive result gave a sensitivity of 91% (88% to 93%) and a specificity of 93% (91% to 94%), compared with a sensitivity of 90% (88% to 93%) and a specificity of 93% (91% to 94%) when subjective assessment was used in all masses. Conclusions The use of the simple rules has the potential to improve the management of women with adnexal masses. In adnexal masses for which the rules yielded an inconclusive result, subjective assessment of ultrasonic findings by an experienced ultrasound examiner was the most accurate diagnostic test; the risk of malignancy index and the two regression models were not useful.

Ovarian cancer prediction in adnexal masses using ultrasound‐based logistic regression models: a temporal and external validation study by the IOTA group

The aims of the study were to temporally and externally validate the diagnostic performance of two logistic regression models containing clinical and ultrasound variables in order to estimate the risk of malignancy in adnexal masses, and to compare the results with the subjective interpretation of ultrasound findings carried out by an experienced ultrasound examiner (‘subjective assessment’).

Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series

BACKGROUND To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS). PATIENTS AND METHODS All patients treated with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility. RESULTS From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients [hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5-11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0-29.3, P=0.0032]. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful. CONCLUSIONS Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored.

Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study.

Objectives To develop a risk prediction model to preoperatively discriminate between benign, borderline, stage I invasive, stage II-IV invasive, and secondary metastatic ovarian tumours. Design Observational diagnostic study using prospectively collected clinical and ultrasound data. Setting 24 ultrasound centres in 10 countries. Participants Women with an ovarian (including para-ovarian and tubal) mass and who underwent a standardised ultrasound examination before surgery. The model was developed on 3506 patients recruited between 1999 and 2007, temporally validated on 2403 patients recruited between 2009 and 2012, and then updated on all 5909 patients. Main outcome measures Histological classification and surgical staging of the mass. Results The Assessment of Different NEoplasias in the adneXa (ADNEX) model contains three clinical and six ultrasound predictors: age, serum CA-125 level, type of centre (oncology centres v other hospitals), maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites. The area under the receiver operating characteristic curve (AUC) for the classic discrimination between benign and malignant tumours was 0.94 (0.93 to 0.95) on temporal validation. The AUC was 0.85 for benign versus borderline, 0.92 for benign versus stage I cancer, 0.99 for benign versus stage II-IV cancer, and 0.95 for benign versus secondary metastatic. AUCs between malignant subtypes varied between 0.71 and 0.95, with an AUC of 0.75 for borderline versus stage I cancer and 0.82 for stage II-IV versus secondary metastatic. Calibration curves showed that the estimated risks were accurate. Conclusions The ADNEX model discriminates well between benign and malignant tumours and offers fair to excellent discrimination between four types of ovarian malignancy. The use of ADNEX has the potential to improve triage and management decisions and so reduce morbidity and mortality associated with adnexal pathology.

Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in patients with Ib1 stage cervical cancer: Analysis of surgical and oncological outcome

AIM To evaluate safety, feasibility and oncological outcome of total laparoscopic radical hysterectomy (TLRH) in patients with early invasive cervical cancer. METHODS Data of patients with Ib1 cervical cancer who underwent TLRH were prospectively collected. Inclusion criteria were: good general condition, tumor size <3 cm, and no evidence of lymph node metastases in imaging study (MRI and/or CT and/or PET). Radical hysterectomy was performed with a PlasmaKinetic tissue management system. Adjuvant therapy was administered according to surgical risk factors. RESULTS Between September 2001 and October 2007 107 patients underwent laparoscopic radical hysterectomy and pelvic lymphadenectomy. Conversion to laparotomy was necessary in 6 patients. Median number of resected pelvic lymph nodes was 26. Median blood loss was 200 ml and median duration of surgery was 305 min. Minor intraoperative complications were registered in two patients, while five patients needed a second surgery for postoperative complications. Thirteen patients had microscopic nodal metastasis. A total of 24 patients received adjuvant therapy. After a median follow-up of 30 months 11 patients had a recurrence; survival rate is 95%. CONCLUSION Total laparoscopic radical hysterectomy, in experienced hands, has to be considerate an adequate and feasible surgical technique. Considering historical data the oncological outcome can be considered comparable to patients treated with laparotomy, as the relapse rate in our population was 11% and the overall survival good.

Adnexal masses difficult to classify as benign or malignant using subjective assessment of gray‐scale and Doppler ultrasound findings: logistic regression models do not help

To develop a logistic regression model that can discriminate between benign and malignant adnexal masses perceived to be difficult to classify by subjective evaluation of gray‐scale and Doppler ultrasound findings (subjective assessment) and to compare its diagnostic performance with that of subjective assessment, serum CA 125 and the risk of malignancy index (RMI).

Strategies to diagnose ovarian cancer: new evidence from phase 3 of the multicentre international IOTA study

Background:To compare different ultrasound-based international ovarian tumour analysis (IOTA) strategies and risk of malignancy index (RMI) for ovarian cancer diagnosis using a meta-analysis approach of centre-specific data from IOTA3.Methods:This prospective multicentre diagnostic accuracy study included 2403 patients with 1423 benign and 980 malignant adnexal masses from 2009 until 2012. All patients underwent standardised transvaginal ultrasonography. Test performance of RMI, subjective assessment (SA) of ultrasound findings, two IOTA risk models (LR1 and LR2), and strategies involving combinations of IOTA simple rules (SRs), simple descriptors (SDs) and LR2 with and without SA was estimated using a meta-analysis approach. Reference standard was histology after surgery.Results:The areas under the receiver operator characteristic curves of LR1, LR2, SA and RMI were 0.930 (0.917–0.942), 0.918 (0.905–0.930), 0.914 (0.886–0.936) and 0.875 (0.853–0.894). Diagnostic one-step and two-step strategies using LR1, LR2, SR and SD achieved summary estimates for sensitivity 90–96%, specificity 74–79% and diagnostic odds ratio (DOR) 32.8–50.5. Adding SA when IOTA methods yielded equivocal results improved performance (DOR 57.6–75.7). Risk of Malignancy Index had sensitivity 67%, specificity 91% and DOR 17.5.Conclusions:This study shows all IOTA strategies had excellent diagnostic performance in comparison with RMI. The IOTA strategy chosen may be determined by clinical preference.

Preoperative staging of cervical cancer: Is 18-FDG-PET/CT really effective in patients with early stage disease?

OBJECTIVE Nodal status is one of the most important findings in patients with early-stage cervical cancer that requires post-surgical adjuvant therapies and influences prognosis of patients. The purpose of this study was to determine the diagnostic accuracy of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) in the detection of nodal metastases. METHODS From 2004 to 2010 women with Ib1-IIa <4cm cervical cancer underwent 18F-FDG-PET/CT followed by radical hysterectomy and pelvic lymphadenectomy in our institution. 18F-FDG-PET/CT images were analyzed and histopathological findings served as the reference standard. Diagnostic performance of 18F-FDG-PET/CT in nodal disease detection was reported in terms of accuracy value. A sub analysis of women with tumor diameter <2cm (group 1) or 2-4cm (group 2) was performed in order to verify the efficacy of 18F-FDG-PET/CT in each group. RESULTS One hundred fifty-nine women were enrolled. 65% had squamous histotype and 51% had grade 3 disease. Median number of nodes dissected was 29 (range 11-61). 28/159 women (18%) showed nodal metastases. Overall patient-based sensitivity, specificity, positive and negative predictive value of 18F-FDG-PET/CT for detection of nodal disease were 32.1%, 96.9%, 69.2%and 87.0% respectively. Among the 97 (61%) women included in group 1, 8 had nodal metastases (8.2%) and 2 was discovered through 18F-FDG-PET/CT (25%), while 20/62 women of the group 2 (32.3%) had nodal involvement, of which 7 (35%) was detected by 18F-FDG-PET/CT. CONCLUSIONS This study showed that 18F-FDG-PET/CT had low sensitivity and had a minimal clinical impact in the pretreatment planning of stage Ib1-IIa <4cm cervical cancer.

Ovarian carcinoma tumor-initiating cells have a mesenchymal phenotype

Solid tumors appear to contain a subpopulation of cells (tumor-initiating cells, TICs) that not only drives and sustains tumor growth, but is possibly responsible for recurrence. We isolated, after enzymatic digestion of primary ovarian carcinoma samples, a subpopulation of cells propagating as non-adherent spheres in medium suitable for tumor stem cells. These cells were able to self-renew in vitro, as suggested by PKH-26 staining studies, were tumorigenic and acquired an epithelial morphology when grown in FBS-supplemented medium, losing their tumorigenic potential. Interestingly, the tumorigenic potential of PKH-26high- and PKH-26neg-sorted cells was similar. These TIC-enriched cultures showed higher levels of genes involved in stemness than differentiated cells derived from them and were more resistant to the cytotoxic effects of some drugs but equally sensitive to others. The higher level of ABCG2 efflux pump could explain increased resistance to taxol and VP16, and higher levels of genes involved in nucleotide excision repair partially explain the resistance to cisplatin. These cells express mesenchymal markers, and epithelial transition could be induced when cultured in differentiating conditions, with a loss of invasive potential. These data suggest that ovarian cancer is a stem cell disease and should help elucidate the role of these cells in the aggressive phenotype of this tumor and find new therapeutic strategies to reduce resistance to current chemotherapeutic drugs.

Analysis of Gene Expression in Early-Stage Ovarian Cancer

Purpose: Gene expression profile was analyzed in 68 stage I and 15 borderline ovarian cancers to determine if different clinical features of stage I ovarian cancer such as histotype, grade, and survival are related to differential gene expression. Experimental Design: Tumors were obtained directly at surgery and immediately frozen in liquid nitrogen until analysis. Glass arrays containing 16,000 genes were used in a dual-color assay labeling protocol. Results: Unsupervised analysis identified eight major patient partitions, one of which was statistically associated to overall survival, grading, and histotype and another with grading and histotype. Supervised analysis allowed detection of gene profiles clearly associated to histotype or to degree of differentiation. No difference was found between borderline and grade 1 tumors. As to recurrence, a subset of genes able to differentiate relapsers from nonrelapsers was identified. Among these, cyclin E and minichromosome maintenance protein 5 were found particularly relevant, as their expression was inversely correlated to progression-free survival (P = 0.00033 and 0.017, respectively). Conclusions: Specific molecular signatures define different histotypes and prognosis of stage I ovarian cancer. Mucinous and clear cells histotypes can be distinguished from the others regardless of tumor grade. Cyclin E and minichromosome maintenance protein 5, whose expression was found previously to be related to a bad prognosis of advanced ovarian cancer, appear to be potential prognostic markers in stage I ovarian cancer too, independent of other pathologic and clinical variables.