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Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review
  1. Luigi Antonio De Vitis1,2,
  2. Gabriella Schivardi1,2,
  3. Giuseppe Caruso1,2,
  4. Caterina Fumagalli3,
  5. Davide Vacirca4,
  6. Maria Teresa Achilarre1,
  7. Alessia Aloisi1,
  8. Annalisa Garbi1,
  9. Vanna Zanagnolo1,
  10. Giovanni Aletti1,5,
  11. Elena Guerini-Rocco6,5,
  12. Andrea Mariani2,
  13. Angelo Maggioni1,
  14. Massimo Barberis4,
  15. Giorgio Bogani7,
  16. Nicoletta Colombo1,8,
  17. Francesco Multinu1 and
  18. Ilaria Betella1
  1. 1Department of Gynecology, Istituto Europeo di Oncologia, Milan, Italy
  2. 2Department of Obstetrics and Gynecology, Division of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Department of Diagnostic Services, Division of Pathology, ASST della Valle Olona, Busto Arsizio, Lombardia, Italy
  4. 4Clinical Unit of Oncogenomics, Division of Pathology, Istituto Europeo di Oncologia, Milan, Italy
  5. 5Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
  6. 6Department of Pathology, Istituto Europeo di Oncologia, Milan, Italy
  7. 7Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  8. 8Faculty of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
  1. Correspondence to Dr Francesco Multinu, Department of Gynecology, Istituto Europeo di Oncologia, Milan, Italy; Francesco.Multinu{at}


Background Endometrial cancers with more than one molecular feature—POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)—are called ‘multiple classifiers’.

Objective To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them.

Methods Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification.

Results Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%.

Conclusions The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing.

  • Endometrial Neoplasms
  • Pathology
  • Uterine Cancer
  • Genital Neoplasms, Female
  • Neoplastic Processes

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Twitter @LuigiDEvitis, @gcarusomd, @Giovanni Aletti, @BoganiGiorgio, @Fmultinu, @IBetella

  • Contributors LADV, GS, GC, IB, FM, and CF conceived, planned, and summarized the project. Cases (with clinical data and outcomes) were contributed by MTA, AA, AG, VZ, GA, AMg, and NC. Dataset assembly/organization by LADV and GS, with molecular methodologies performed by CF, EG-R, MB, DV, AMr, GB, and NC who provided intellectual contribution and edits. LADV and FM performed the statistical analyses. All authors contributed to manuscript writing and editing. IB and FM were responsible for the overall content as guarantors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.