Prognostic significance of isolated tumor cells and nodal tumor burden in endometrial cancer: a population-based cohort study

Authors

  • Andrei Chilianu Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0009-0009-2267-1829
  • Charlotta Riese Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden https://orcid.org/0009-0007-1947-0060
  • Mahmood UL Hassan Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden https://orcid.org/0000-0003-2889-0263
  • Jaiteh Darbo Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden
  • Henrik Falconer Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0003-4427-9421
  • Linda Eriksson Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
  • Sahar Salehi Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0002-5426-2570

DOI:

https://doi.org/10.2340/1651-226X.2026.45813

Keywords:

Endometrial neoplasms, sentinel lymph node biopsy, lymphatic metastases, micrometastasis, prognosis, Survival Analysis, isolated tumour cells

Abstract

Background and purpose: Since the introduction of sentinel lymph node biopsy, nodal assessment has expanded to nearly all women with endometrial cancer. However, evidence on the prognostic significance of isolated tumor cells (ITCs) and nodal tumor burden remains limited. We therefore investigated the association of ITCs and nodal tumor burden with survival.
Patients and methods: This cohort study included women with endometrial cancer who underwent surgery in Region Stockholm–Gotland, Sweden, between 2010 and 2024, and either underwent sentinel lymph node biopsy or were registered as having lymph node metastases (FIGO stage IIIC). Nodal dissemination was categorized as bulky, macro-, micro-metastases, or ITCs. Overall survival (OS) and cancer-specific survival (CSS) were evaluated using multivariable Cox regression in two separate analyses: (1) ITCs versus node-negative patients and (2) nodal tumor burden (bulky, macro-, micro-metastases) among node-positive patients.
Results: Among 1219 patients, 310 (25%) had nodal dissemination, including 250 with nodal metastases and 60 with ITCs. No significant difference in OS was observed between patients with ITCs and node-negative patients (Hazard ratio [HR] 1.94, 95% confidence interval [CI] 0.75–5.06). Adjuvant therapy was more frequent among patients with ITCs (47% vs. 11%).
In patients with nodal metastases, no clear OS differences were observed by nodal burden. Compared with micrometastases, survival was similar for macrometastases (HR 0.95, 95% CI 0.50–1.81) and bulky metastases (HR 1.19, 95% CI 0.64–2.21). Age > 68 years and p53 mutation were associated with worse survival. CSS analyses yielded similar findings, with no significant differences observed in either comparison.
Interpretation: Neither ITCs nor greater nodal burden was clearly associated with survival after adjustment for clinical and molecular factors. Survival appeared to be influenced by patient and tumor characteristics, although estimates were imprecise and modest associations cannot be excluded.

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References

Gu B, Shang X, Yan M, Li X, Wang W, Wang Q, et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990–2019. Gynecol Oncol. 2021;161(2):573–80 DOI: https://doi.org/10.1016/j.ygyno.2021.01.036

Filho AM, Laversanne M, Ferlay J, Colombet M, Piñeros M, Znaor A, et al. The GLOBOCAN 2022 cancer estimates: data sources, methods, and a snapshot of the cancer burden worldwide. Int J Cancer. 2025;156(7):1336–46 DOI: https://doi.org/10.1002/ijc.35278

Concin N, Matias-Guiu X, Cibula D, Colombo N, Creutzberg CL, Ledermann J, et al. ESGO-ESTRO-ESP guidelines for the management of patients with endometrial carcinoma: update 2025. Lancet Oncol. 2025;26(8):e423–35 DOI: https://doi.org/10.1016/S1470-2045(25)00167-6

Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A gynecologic oncology group study. Cancer. 1987;60(8 Suppl):2035–41 DOI: https://doi.org/10.1002/1097-0142(19901015)60:8+<2035::AID-CNCR2820601515>3.0.CO;2-8

Prat J. Prognostic parameters of endometrial carcinoma. Hum Pathol. 2004;35(6):649–62 DOI: https://doi.org/10.1016/j.humpath.2004.02.007

Olawaiye AB, Cotler J, Cuello MA, Bhatla N, Okamoto A, Wilailak S, et al. FIGO staging for carcinoma of the vulva: 2021 revision. Int J Gynaecol Obstet. 2021;155(1):43–7 DOI: https://doi.org/10.1002/ijgo.13880

Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472–92 DOI: https://doi.org/10.3322/caac.21409

Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer – major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290–303 DOI: https://doi.org/10.3322/caac.21393

Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100(23):1707–16 DOI: https://doi.org/10.1093/jnci/djn397

Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373(9658):125–36 DOI: https://doi.org/10.1016/S0140-6736(08)61766-3

Persson J, Salehi S, Bollino M, Lonnerfors C, Falconer H, Geppert B. Pelvic Sentinel lymph node detection in High-Risk Endometrial Cancer (SHREC-trial) – the final step towards a paradigm shift in surgical staging. Eur J Cancer. 2019;116:77–85 DOI: https://doi.org/10.1016/j.ejca.2019.04.025

Rossi EC, Kowalski LD, Scalici J, Cantrell L, Schuler K, Hanna RK, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384–92 DOI: https://doi.org/10.1016/S1470-2045(17)30068-2

Cusimano MC, Vicus D, Pulman K, Maganti M, Bernardini MQ, Bouchard-Fortier G, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156(2):157–64 DOI: https://doi.org/10.1001/jamasurg.2020.5060

Kim CH, Soslow RA, Park KJ, Barber EL, Khoury-Collado F, Barlin JN, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer. 2013;23(5):964–70 DOI: https://doi.org/10.1097/IGC.0b013e3182954da8

de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, et al. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17(8):1114–26 DOI: https://doi.org/10.1016/S1470-2045(16)30120-6

Herrera FG, Cruz OS, Achtari C, Bourhis J, Ozsahin M. Long-term outcome and late side effects in endometrial cancer patients treated with surgery and postoperative radiation therapy. Ann Surg Oncol. 2014;21(7):2390–7 DOI: https://doi.org/10.1245/s10434-014-3622-9

Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC study group. Post operative radiation therapy in endometrial carcinoma. Lancet. 2000;355(9213):1404–11 DOI: https://doi.org/10.1016/S0140-6736(00)02139-5

Nout RA, Smit VT, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375(9717):816–23 DOI: https://doi.org/10.1016/S0140-6736(09)62163-2

Miller DS, Filiaci VL, Mannel RS, Cohn DE, Matsumoto T, Tewari KS, et al. Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol. 2020;38(33):3841–50 DOI: https://doi.org/10.1200/JCO.20.01076

Matsuo K, Chen L, Neuman MK, Klar M, Carlson JW, Roman LD, et al. Lymph node isolated tumor cells in patients with endometrial cancer. JAMA Netw Open. 2024;7(3):e240988 DOI: https://doi.org/10.1001/jamanetworkopen.2024.0988

Zhuang Y, Xu Y, Deng P, Wang S, Nie H, Yang H. The prognostic significance and role of adjuvant therapy for low-volume nodal metastasis in apparent early stage endometrial cancer: an updated systematic review and meta-analysis. J Gynecol Oncol. 2025;36(5):e67 DOI: https://doi.org/10.3802/jgo.2025.36.e67

von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453–7 DOI: https://doi.org/10.1016/S0140-6736(07)61602-X

American Joint Committee on Cancer Breast. AJCC cancer staging manual. 8th ed. New York, NY: Springer; 2017. p. 589.

R Core Team. R: A language and environment for statistical computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; 2024. [cited 2026 July 7]. Available from: https://www.R-project.org/

Houvenaeghel G, Classe JM, Garbay JR, Giard S, Cohen M, Faure C, et al. Prognostic value of isolated tumor cells and micrometastases of lymph nodes in early-stage breast cancer: a French sentinel node multicenter cohort study. Breast. 2014;23(5):561–6 DOI: https://doi.org/10.1016/j.breast.2014.04.004

van der Heiden-van der Loo M, Schaapveld M, Ho VK, Siesling S, Rutgers EJ, Peeters PH. Outcomes of a population-based series of early breast cancer patients with micrometastases and isolated tumour cells in axillary lymph nodes. Ann Oncol. 2013;24(11):2794–801 DOI: https://doi.org/10.1093/annonc/mdt243

de Boer M, van Deurzen CH, van Dijck JA, Borm GF, van Diest PJ, Adang EM, et al. Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009;361(7):653–63 DOI: https://doi.org/10.1056/NEJMoa0904832

Bollino M, Geppert B, Lönnerfors C, Måsbäck A, Kasselaki I, Persson J. Prevalence and size of pelvic sentinel lymph node metastases in endometrial cancer. Eur J Cancer. 2024;209:114265 DOI: https://doi.org/10.1016/j.ejca.2024.114265

Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(3):744–51 DOI: https://doi.org/10.1016/j.ygyno.2003.11.048

Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373(9658):137–46 DOI: https://doi.org/10.1016/S0140-6736(08)61767-5

Matei DE, Enserro DM, Randall ME, Mutch D, Small W, DiSilvestro PA, et al. Long-term follow-up and overall survival in NRG258, a randomized phase III trial of chemoradiation versus chemotherapy for locally advanced endometrial carcinoma. J Clin Oncol. 2025;43(9):1055–60 DOI: https://doi.org/10.1200/JCO.24.01121

Susumu N, Sagae S, Udagawa Y, Niwa K, Kuramoto H, Satoh S, et al. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008;108(1):226–33 DOI: https://doi.org/10.1016/j.ygyno.2007.09.029

Matsuo K, Agarwal J, Chen L, Furey KB, Song BB, Pino C, et al. Histology-specific prognostic significance of isolated tumor cells, micrometastases, and macrometastases in endometrial cancer. Gynecol Oncol. 2025;194:51–9 DOI: https://doi.org/10.1016/j.ygyno.2025.02.012

Schivardi G, Caruso G, De Vitis LA, Cucinella G, Multinu F, Zanagnolo V, et al. Impact of molecular classification on recurrence risk in endometrial cancer patients with lymph node metastasis: multicenter retrospective study. Int J Gynecol Cancer. 2024;34(10):1561–9 DOI: https://doi.org/10.1136/ijgc-2024-005672

Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73 DOI: https://doi.org/10.1038/nature12113

Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 2015;113(2):299–310 DOI: https://doi.org/10.1038/bjc.2015.190

Talhouk A, McConechy MK, Leung S, Yang W, Lum A, Senz J, et al. Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017;123(5):802–13 DOI: https://doi.org/10.1002/cncr.30496

Kommoss S, McConechy MK, Kommoss F, Leung S, Bunz A, Magrill J, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol. 2018;29(5):1180–8 DOI: https://doi.org/10.1093/annonc/mdy058

Wakkerman FC, Wu J, Putter H, Jürgenliemk-Schulz IM, Jobsen JJ, Lutgens L, et al. Prognostic impact and causality of age on oncological outcomes in women with endometrial cancer: a multimethod analysis of the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials. Lancet Oncol. 2024;25(6):779–89 DOI: https://doi.org/10.1016/S1470-2045(24)00142-6

Benedetti Panici P, Basile S, Salerno MG, Di Donato V, Marchetti C, Perniola G, et al. Secondary analyses from a randomized clinical trial: age as the key prognostic factor in endometrial carcinoma. Am J Obstet Gynecol. 2014;210(4):363.e1–10 DOI: https://doi.org/10.1016/j.ajog.2013.12.025

Berek JS, Matias-Guiu X, Creutzberg C, Fotopoulou C, Gaffney D, Kehoe S, et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383–94 DOI: https://doi.org/10.1002/ijgo.14923

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Published

2026-08-11

How to Cite

Chilianu, A., Riese, C., UL Hassan, M., Darbo, J., Falconer, H., Eriksson, L., & Salehi, S. (2026). Prognostic significance of isolated tumor cells and nodal tumor burden in endometrial cancer: a population-based cohort study. Acta Oncologica, 65, 702–712. https://doi.org/10.2340/1651-226X.2026.45813

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