Prognostic impact of low-volume nodal metastases in endometrial cancer: a systematic review of molecular subtypes.

Abstract

<h4>Introduction</h4>Endometrial cancer (EC) is the most common gynecologic malignancy, with lymph node metastases (LNM) serving as a key prognostic factor. Low-volume metastases (LVM), including micrometastases (MM; >0.2-≤2 mm) and isolated tumor cells (ITCs; ≤0.2 mm), detected via sentinel lymph node (SLN) ultrastaging, remain controversial regarding their clinical impact. This systematic review evaluates the prognostic significance of LVM, stratified by The Cancer Genome Atlas (TCGA) molecular subtypes.<h4>Methods</h4>Following PRISMA guidelines, this study conducted a systematic review (PROSPERO: CRD420251067512) of research published from 2013 to 2025. Inclusion criteria comprised EC patients with LVM who underwent nodal staging (SLN or lymphadenectomy) and molecular classification. Outcomes included progression-free survival (PFS), overall survival (OS), recurrence, and the impact of adjuvant therapy. Risk of bias was assessed using the Newcastle-Ottawa Scale and ROBINS-I.<h4>Results</h4>Ten studies (<i>n</i> = 4,482 patients) were included. Micrometastases were associated with worse PFS (HR 2.45, 95% CI 1.89-3.18) and OS (HR 1.75, 95% CI 1.40-2.18), particularly in p53-abnormal (p53abn) subtypes (HR 2.9, 95% CI 2.3-3.7). ITCs showed minimal prognostic impact (PFS HR 1.3, 95% CI 1.0-1.6; OS HR 1.1, 95% CI 0.88-1.37). SLN mapping with ultrastaging improved detection (72% increase vs. H&E) without compromising survival compared to lymphadenectomy. Molecular stratification revealed that POLE-ultramutated tumors retained an excellent prognosis despite the presence of LVM.<h4>Discussion</h4>The prognostic relevance of LVM varies substantially by metastatic burden and molecular subtype. Micrometastases may warrant escalation of adjuvant therapy, whereas ITCs may not require systemic treatment in favorable molecular subtypes. SLN ultrastaging should be standardized, and integration of TCGA classification into routine clinical decision-making is essential. Future clinical trials must validate subtype-specific management strategies.<h4>Systematic review registration</h4>PROSPERO, identifier ID: CRD420251067512.