Update of the ADNEX risk model (ADNEX2) to diagnose ovarian cancer in surgically and conservatively managed patients with an adnexal mass: multicentre prospective cohort study

Objective: The ADNEX ultrasound-based prediction model estimates the probability that an adnexal mass is benign, borderline, stage I primary invasive, stage II-IV primary invasive, or secondary metastatic. ADNEX was developed on patients managed surgically. We aimed to update ADNEX to ADNEX2 using more recent data on both surgically and conservatively managed patients. ADNEX2 is designed for use in patients in whom the benign descriptors (BDs), a set of ultrasound profiles with an estimated risk of malignancy below 1%, do not apply. Design: Secondary analysis of a multicentre prospective cohort study. Setting: 17 oncology and non-oncology centres from 8 European countries. Participants: Patients with a newly detected adnexal mass recruited between 2012 and 2016 who were managed surgically or conservatively with clinical and ultrasound follow-up. Interventions: ADNEX2 uses the same predictors as ADNEX (age, type of centre, lesion diameter, proportion of solid tissue, number of papillary projections, >10 cyst locules, ascites and acoustic shadows and CA125). Model updating involved logistic recalibration followed by Bayesian refitting. Validation was based on leave-one-centre-out cross-validation. ADNEX2 and ADNEX include CA125 but also work without CA125. Main outcome measures: Model performance regarding discrimination (AUC), calibration (plots and observed:expected, O:E, ratio), and clinical utility (net benefit). Results: Of 6847 patients, 4625 (68%) had a benign tumour, 1710 (25%) had a malignant tumour, while tumour outcome was uncertain for 512 (7%) patients. BDs applied in 2190 (32%) patients, of whom 0.5% (95% CI, 0.2%-0.9%) had a malignancy. A two-step strategy using BDs followed by ADNEX2 had an AUC of 0.95 (0.94-0.96) to distinguish benign from malignant tumours. When evaluated on 4657 patients in whom BDs did not apply, ADNEX2 had an AUC of 0.93 (0.91-0.94). The two-step strategy with ADNEX2 was better calibrated than the two-step strategy with ADNEX (O:E ratio of 1.05 versus 1.14) and had marginally higher clinical utility. Not including available CA125 values in ADNEX2 reduced the ability to distinguish stage II-IV primary invasive tumours from other invasive malignancies. Conclusions: ADNEX2 is better calibrated than ADNEX. CA125 measurement is not crucial to estimate the risk of malignancy, but is recommended to estimate the risk of malignant subtypes. Trial registration: clinicaltrials.gov NCT01698632 .

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Journal
medRxiv
Published
2026-10-26
DOI
https://doi.org/10.64898/2026.10.23.26365247
Primary Topic
Ovarian cancer diagnosis and treatment
Type
preprint

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preprint

Update of the ADNEX risk model (ADNEX2) to diagnose ovarian cancer in surgically and conservatively managed patients with an adnexal mass: multicentre prospective cohort study

Cristina Taliento, Fatima Regina Abreu Alves, Dirk Timmerman, S. Guerriero et al.
medRxiv
Ovarian cancer diagnosis and treatment
preprint

Update of the ADNEX risk model (ADNEX2) to diagnose ovarian cancer in surgically and conservatively managed patients with an adnexal mass: multicentre prospective cohort study

Cristina Taliento, Fatima Regina Abreu Alves, Dirk Timmerman, S. Guerriero, Joie Ensor, Antonia Carla Testa, E. Epstein, D. Fischerová, Tom Bourne, Floriana Mascilini, Lasai Barreñada, Juan Luis Alcázar, F. Moro, Federica Pozzati, Marek Jerzy Kudla, Lil Valentin, P. Sladkevicius, Robert Fruscio, Chiara Landolfo, L. Jokubkiene, Laure Wynants, Dorella Franchi, Ashleigh Ledger, Francesca Buonomo, Valentina Chiappa, Jolien Ceusters, Wouter Froyman, Ben Van Calster, Maria Elisabetta Coccia, Caroline Van Holsbeke, Francesco PG Leone
preprint en

Abstract

Objective: The ADNEX ultrasound-based prediction model estimates the probability that an adnexal mass is benign, borderline, stage I primary invasive, stage II-IV primary invasive, or secondary metastatic. ADNEX was developed on patients managed surgically. We aimed to update ADNEX to ADNEX2 using more recent data on both surgically and conservatively managed patients. ADNEX2 is designed for use in patients in whom the benign descriptors (BDs), a set of ultrasound profiles with an estimated risk of malignancy below 1%, do not apply. Design: Secondary analysis of a multicentre prospective cohort study. Setting: 17 oncology and non-oncology centres from 8 European countries. Participants: Patients with a newly detected adnexal mass recruited between 2012 and 2016 who were managed surgically or conservatively with clinical and ultrasound follow-up. Interventions: ADNEX2 uses the same predictors as ADNEX (age, type of centre, lesion diameter, proportion of solid tissue, number of papillary projections, >10 cyst locules, ascites and acoustic shadows and CA125). Model updating involved logistic recalibration followed by Bayesian refitting. Validation was based on leave-one-centre-out cross-validation. ADNEX2 and ADNEX include CA125 but also work without CA125. Main outcome measures: Model performance regarding discrimination (AUC), calibration (plots and observed:expected, O:E, ratio), and clinical utility (net benefit). Results: Of 6847 patients, 4625 (68%) had a benign tumour, 1710 (25%) had a malignant tumour, while tumour outcome was uncertain for 512 (7%) patients. BDs applied in 2190 (32%) patients, of whom 0.5% (95% CI, 0.2%-0.9%) had a malignancy. A two-step strategy using BDs followed by ADNEX2 had an AUC of 0.95 (0.94-0.96) to distinguish benign from malignant tumours. When evaluated on 4657 patients in whom BDs did not apply, ADNEX2 had an AUC of 0.93 (0.91-0.94). The two-step strategy with ADNEX2 was better calibrated than the two-step strategy with ADNEX (O:E ratio of 1.05 versus 1.14) and had marginally higher clinical utility. Not including available CA125 values in ADNEX2 reduced the ability to distinguish stage II-IV primary invasive tumours from other invasive malignancies. Conclusions: ADNEX2 is better calibrated than ADNEX. CA125 measurement is not crucial to estimate the risk of malignancy, but is recommended to estimate the risk of malignant subtypes. Trial registration: clinicaltrials.gov NCT01698632 .

medRxiv
Birmingham City University (GB), Medical University of Silesia (PL), University of Cagliari (IT), Malmö University (SE), Lund University (SE), University of Milan (IT), University of Ferrara (IT), Charles University (CZ), Heidelberg University (DE), IRCCS Materno Infantile Burlo Garofolo (IT), University Hospital Heidelberg (DE), Agostino Gemelli University Polyclinic (IT), Karolinska Institutet (SE), University Medical Center Utrecht (NL), Luigi Sacco Hospital (IT), Stockholm South General Hospital (SE), Queen Charlotte's and Chelsea Hospital (GB), Azienda Ospedaliero-Universitaria Cagliari (IT), Clinica Universidad de Navarra (ES), Skåne University Hospital (SE), Ziekenhuis Oost-Limburg (BE), Hospital de Santa Maria (PT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), General University Hospital in Prague (CZ), Care and Public Health Research Institute (NL), University of Florence (IT), Imperial College London (GB), European Institute of Oncology (IT), University of Milano-Bicocca (IT), University of Birmingham (GB), KU Leuven (BE)
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