BACKGROUND: In cervical cancer, presence of lymph-node macrometastases (MAC) is a major prognostic factor and an indication for adjuvant treatment. However, since clinical impact of micrometastases (MIC) and isolated tumor-cells (ITC) remains controversial, we sought to identify a cut-off value for the metastasis size not associated with negative prognosis. METHODS: We analyzed data from 967 cervical cancer patients (T1a1L1-T2b) registered in the SCCAN (Surveillance in Cervical CANcer) database, who underwent primary surgical treatment, including sentinel lymph-node (SLN) biopsy with pathological ultrastaging. The size of SLN metastasis was considered a continuous variable and multiple testing was performed for cut-off values of 0.01-1.0 mm. Disease-free survival (DFS) was compared between N0 and subgroups of N1 patients defined by cut-off ranges. RESULTS: LN metastases were found in 172 (18%) patients, classified as MAC, MIC, and ITC in 79, 54, and 39 patients, respectively. DFS was shorter in patients with MAC (HR 2.20, P = 0.003) and MIC (HR 2.87, P < 0.001), while not differing between MAC/MIC (P = 0.484). DFS in the ITC subgroup was neither different from N0 (P = 0.127) nor from MIC/MAC subgroups (P = 0.449). Cut-off analysis revealed significantly shorter DFS compared to N0 in all subgroups with metastases ≥0.4 mm (HR 2.311, P = 0.04). The significance of metastases <0.4 mm could not be assessed due to limited statistical power (<80%). We did not identify any cut-off for the size of metastasis with significantly better prognosis than the rest of N1 group. CONCLUSIONS: In cervical cancer patients, the presence of LN metastases ≥0.4 mm was associated with a significant negative impact on DFS and no cut-off value for the size of metastasis with better prognosis than N1 was found. Traditional metastasis stratification based on size has no clinical implication.

Department of Gynaecology and Obstetrics University Hospital Pilsen Charles University Prague Czech Republic

Department of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer Center Houston USA

Department of Gynecologic Oncology Hospital Italiano de Buenos Aires Instituto Universitario Hospital Italiano Buenos Aires Argentina

Department of Gynecological Oncology Amsterdam University Medical Center Center for Gynecological Oncology Amsterdam Amsterdam Netherlands

Department of Gynecological Surgery National Institute of Neoplastic Diseases Lima Peru

Department of Obstetrics and Gynecology Faculty of Medicine University Hospital and University of Ostrava Ostrava Czech Republic

Department of Obstetrics and Gynecology General Teaching Hospital and The 1st Faculty of Medicine of Charles University Prague Prague Czech Republic

Department of Obstetrics and Gynecology University of Milano Bicocca Department of Obstetrics and Gynecology Gynaecologic Oncology Surgical Unit ASST Monza San Gerardo Hospital Monza Italy

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pelvic Cancer Karolinska University Hospital and Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Department of Surgery Memorial Sloan Kettering Cancer Center New York USA

Gynecologic Oncology Unit La Paz University Hospital IdiPAZ Madrid Spain

Gynecology Oncology Center National Institute of Cancerology Mexico Ciudad De Mexico Mexico

Institute of Biostatistics and Analyses Institute of Biostatistics and Analyses Faculty of Medicine Masaryk University Brno Czech Republic

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MILACC study: could undetected lymph node micrometastases have impacted recurrence rate in the LACC trial?