Prognostic Value of Tumor Budding and Worst Pattern of Invasion in Clinically Node-Negative Early-Stage Lip and Oral Cavity Squamous Cell Carcinoma: A Systematic Review

Background: Early-stage squamous cell carcinoma of the lip and oral cavity may behave aggressively despite clinically negative cervical lymph nodes. Tumor budding (TB) and worst pattern of invasion (WPOI) have been proposed as histopathological markers of invasive behavior, but their prognostic value in cT1–2N0M0 disease remains uncertain. Methods: This PRISMA 2020 systematic review included studies published as eligible full-text journal articles up to 25 April 2026 and was informed by REMARK and guidance for systematic reviews of prognostic factor studies. PubMed and Scopus were searched as bibliographic databases, supplemented by ScienceDirect, Semantic Scholar, and backward and forward citation searching. Eligible studies assessed TB and/or WPOI in resection specimens from surgically treated cT1–2N0M0 lip/oral cavity squamous cell carcinoma and reported nodal, recurrence, or eligible survival outcomes. Risk of bias was evaluated using the Quality In Prognosis Studies (QUIPS) tool. Results: Thirty-eight reports met eligibility criteria; linked or partially overlapping cohorts were treated as related evidence to avoid double counting. Higher-risk WPOI and high-grade TB were associated with cervical nodal disease, locoregional recurrence, and adverse survival across multiple reports, although adjusted effects varied. Eligible survival outcomes included disease-free survival, recurrence-free survival, disease-specific/cancer-specific survival, and overall survival; progression-free survival was excluded. Conclusions: TB and WPOI may provide complementary postoperative prognostic information in clinically node-negative early-stage lip and oral cavity squamous cell carcinoma. Heterogeneity in definitions, thresholds, cervical management, endpoints, and statistical adjustment precluded a single pooled estimate and limits immediate clinical implementation. Neither marker should currently be used as an isolated determinant of treatment decisions.