{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:27:27Z","timestamp":1787128047916,"version":"build-2736575974"},"reference-count":26,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003197","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG17678"],"award-info":[{"award-number":["IG17678"]}],"id":[{"id":"10.13039\/501100003197","id-type":"DOI","asserted-by":"publisher"}]},{"award":["IG17678"],"award-info":[{"award-number":["IG17678"]}],"id":[{"id":"https:\/\/ror.org\/02g2x7380","id-type":"ROR","asserted-by":"publisher"}]},{"name":"ENS@T","award":["F2-2010-259735"],"award-info":[{"award-number":["F2-2010-259735"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["314061271"],"award-info":[{"award-number":["314061271"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"award":["314061271"],"award-info":[{"award-number":["314061271"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]},{"name":"French Ministry of Health","award":["PHRC-K 2010-P100139"],"award-info":[{"award-number":["PHRC-K 2010-P100139"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Adrenocortical carcinoma (ACC) is a rare tumor. Diagnosis relies on combined histopathological criteria that, in a multifactorial scoring system, may suggest malignancy. The recent ADIUVO trial, a multicenter trial randomizing ACC patients between mitotane treatment or surveillance only, demonstrated that patients with localized, low-grade ACC (Ki67 labeling index (LI) \u2264 10%) have a better prognosis than historically anticipated, questioning the routine use of adjuvant mitotane. This post hoc analysis aimed to investigate whether automated, centralized Ki67 LI assessment improves prognostic stratification beyond expert manual assessment in low-risk ACC patients enrolled in the original ADIUVO trial. Methods: Ki67 LI was centrally reassessed in 70 ADIUVO patients by digitizing slides and applying an automated algorithm to manually selected hotspots. Primary endpoints were correlation between methods and the impact of automated scoring on recurrence-free survival (RFS) and overall survival (OS). Results: Automated Ki67 LI assessment was feasible in 47 patients. Manual and automated Ki67 LI values showed good agreement (mean 5.6 \u00b1 3.1% vs. 5.4 \u00b1 5.3%). Automated scoring identified eight patients with KI67 LI &gt; 10%. In this subgroup, RFS and OS did not differ significantly between patients treated with mitotane and those under surveillance. Patients with an automated Ki67 LI &gt; 10% had larger tumors (median 16.0 cm vs. 7.0 cm, p = 0.003). Conclusions: Our findings support the original ADIUVO results and support continued use of manual expert Ki67 LI scoring. This traditional approach remains robust and pragmatic for most clinical settings, especially where automated systems are not readily accessible.<\/jats:p>","DOI":"10.3390\/cancers18162678","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:12:11Z","timestamp":1787069531000},"page":"2678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Does Automated Versus Manual Ki67 Labeling Index Assessment Influence Risk Stratification in Patients with Localized Adrenocortical Carcinoma? Lessons from the ADIUVO Trial"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8926-1140","authenticated-orcid":false,"given":"Marijn A.","family":"Vermeulen","sequence":"first","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linde M.","family":"Amelung","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, 3584CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otilia","family":"Kimpel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wurzburg, 97080 Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Dischinger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wurzburg, 97080 Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Basile","sequence":"additional","affiliation":[{"name":"Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3034-5598","authenticated-orcid":false,"given":"Darko","family":"Kastelan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, University Hospital Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Lasolle","sequence":"additional","affiliation":[{"name":"Federation d\u2019Endocrinologie, Hospices Civils de Lyon, University de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Bourdeau","sequence":"additional","affiliation":[{"name":"Service d\u2019Endocrinologie, D\u00e9partement de M\u00e9decine, Centre Hospitalier de l\u2019Universite de Montr\u00e9al (CHUM), Montreal, QC H2X 3E4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"N\u00f6lting","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5545-550X","authenticated-orcid":false,"given":"Paola","family":"Loli","sequence":"additional","affiliation":[{"name":"Endocrinology, Clinica San Carlo, 20037 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magalie","family":"Haissaguerre","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Endocrine Oncology, Haut Leveque Hospital, University Hospital of Bordeaux, 33604 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3956-0043","authenticated-orcid":false,"given":"Alfredo","family":"Berruti","sequence":"additional","affiliation":[{"name":"Medical Oncology, ASST-Spedali Civili, University of Brescia Comprehensive Cancer Center, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6170-6398","authenticated-orcid":false,"given":"Martin","family":"Fassnacht","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wurzburg, 97080 Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-2851","authenticated-orcid":false,"given":"Massimo","family":"Terzolo","sequence":"additional","affiliation":[{"name":"Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6871-1296","authenticated-orcid":false,"given":"Ronald R.","family":"de Krijger","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, 3584CS Utrecht, The Netherlands"},{"name":"University Medical Center Utrecht, 3584CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1210\/jc.2014-3182","article-title":"Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection","volume":"100","author":"Beuschlein","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.eprac.2023.10.004","article-title":"Incidence and Geographical Distribution of Adrenocortical Carcinoma: Retrospective Analysis of a State Cancer Registry","volume":"30","author":"Griffin","year":"2024","journal-title":"Endocr. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.1016\/j.ejca.2013.02.034","article-title":"Adrenocortical carcinoma: A population-based study on incidence and survival in the Netherlands since 1993","volume":"49","author":"Kerkhofs","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.surg.2018.04.068","article-title":"Longitudinal patterns of recurrence in patients with adrenocortical carcinoma","volume":"165","author":"Glenn","year":"2019","journal-title":"Surgery"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"ii12","DOI":"10.1093\/ejendo\/lvaf063","article-title":"EndoCompass project: Research roadmap for adrenal and cardiovascular endocrinology","volume":"193","author":"Husebye","year":"2025","journal-title":"Eur. J. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1016\/j.annonc.2020.08.2099","article-title":"Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Fassnacht","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1097\/00000478-198403000-00001","article-title":"Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors","volume":"8","author":"Weiss","year":"1984","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1097\/00000478-200307000-00001","article-title":"Adrenal cortical neoplasms in the pediatric population: A clinicopathologic and immunophenotypic analysis of 83 patients","volume":"27","author":"Wieneke","year":"2003","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1177\/106689690401200304","article-title":"Adrenocortical oncocytic tumors: Report of 10 cases and review of the literature","volume":"12","author":"Bisceglia","year":"2004","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1210\/jc.2016-2894","article-title":"Long-Term Outcomes of Adjuvant Mitotane Therapy in Patients With Radically Resected Adrenocortical Carcinoma","volume":"102","author":"Berruti","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.jamcollsurg.2015.12.013","article-title":"Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A 13-Institution Study by the US Adrenocortical Carcinoma Group","volume":"222","author":"Postlewait","year":"2016","journal-title":"J. Am. Coll. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9362108","DOI":"10.1155\/2018\/9362108","article-title":"Benefits of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis","volume":"2018","author":"Tang","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1530\/EJE-18-0923","article-title":"Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence","volume":"180","author":"Calabrese","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1530\/EJE-18-0608","article-title":"European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors","volume":"179","author":"Fassnacht","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1210\/jc.2006-1007","article-title":"Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma","volume":"91","author":"Fassnacht","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1210\/jc.2019-00029","article-title":"Adjuvant Radiation Improves Recurrence-Free Survival and Overall Survival in Adrenocortical Carcinoma","volume":"104","author":"Gharzai","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1530\/EJE-21-0510","article-title":"S-GRAS score for prognostic classification of adrenocortical carcinoma: An international, multicenter ENSAT study","volume":"186","author":"Elhassan","year":"2021","journal-title":"Eur. J. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/S2213-8587(23)00193-6","article-title":"Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): An international, multicentre, open-label, randomised, phase 3 trial and observational study","volume":"11","author":"Terzolo","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/his.14356","article-title":"The human-in-the-loop: An evaluation of pathologists\u2019 interaction with artificial intelligence in clinical practice","volume":"79","author":"Molin","year":"2021","journal-title":"Histopathology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1097\/PAI.0000000000001188","article-title":"Ki-67 Testing in Breast Cancer: Assessing Variability With Scoring Methods and Specimen Types and the Potential Subsequent Impact on Therapy Eligibility","volume":"32","author":"Bocklage","year":"2024","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"129","DOI":"10.4132\/jptm.2015.12.24","article-title":"Interobserver Variability of Ki-67 Measurement in Breast Cancer","volume":"50","author":"Chung","year":"2016","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s12022-020-09654-x","article-title":"Clinical Impact of Pathological Features Including the Ki-67 Labeling Index on Diagnosis and Prognosis of Adult and Pediatric Adrenocortical Tumors","volume":"32","author":"Almeida","year":"2021","journal-title":"Endocr. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1158\/1078-0432.CCR-14-1283","article-title":"Standardized Ki67 Diagnostics Using Automated Scoring--Clinical Validation in the GeparTrio Breast Cancer Study","volume":"21","author":"Klauschen","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e40193","DOI":"10.1016\/j.heliyon.2024.e40193","article-title":"Improving the accuracy of reporting Ki-67 IHC by using an AI tool","volume":"10","author":"Saraf","year":"2024","journal-title":"Heliyon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1210\/clinem\/dgaf082","article-title":"Does adjuvant mitotane impact cure rates in adrenocortical carcinoma? Insights from the ICARO-GETTHI\/SEEN registry","volume":"110","author":"Iglesias","year":"2025","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/s13000-014-0216-6","article-title":"Automated Selection of Hotspots (ASH): Enhanced automated segmentation and adaptive step finding for Ki67 hotspot detection in adrenal cortical cancer","volume":"9","author":"Lu","year":"2014","journal-title":"Diagn. Pathol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/16\/2678\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:08:28Z","timestamp":1787126908000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/16\/2678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":26,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cancers18162678"],"URL":"https:\/\/doi.org\/10.3390\/cancers18162678","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]}}}