Simple SummaryPreoperative mediastinal staging plays a crucial role in determining the appropriate treatment strategy for patients with stage IIIA-N2 disease, but an optimal treatment strategy has yet to be established. Invasive mediastinal staging is indicated in approximately 30% of patients with suspected NSCLC. In general, if proven N2 disease is present, induction therapy is prioritized in order to downstage and achieve a better prognosis. In the absence of N2 disease, surgical resection with mediastinal lymphadenectomy is the most appropriate treatment option. Nevertheless, unforeseen N2 (uN2) disease, also called unexpected or surprise N2, can still be found during or after surgery despite current preoperative mediastinal staging showing N0 or N1 disease. As preoperative mediastinal staging improved over time, the prevalence of uN2 changed. The aim of this study is to determine the prevalence of true uN2 disease and its characteristics. A secondary objective is to identify its significance for long-term outcomes.AbstractPatients with unforeseen N2 (uN2) disease are traditionally considered to have an unfavorable prognosis. As preoperative and intraoperative mediastinal staging improved over time, the prevalence of uN2 changed. In this review, the current evidence on uN2 disease and its prevalence will be evaluated. A systematic literature search was performed to identify all studies or completed, published trials that included uN2 disease until 6 April 2023, without language restrictions. The Newcastle-Ottawa Scale (NOS) was used to score the included papers. A total of 512 articles were initially identified, of which a total of 22 studies met the predefined inclusion criteria. Despite adequate mediastinal staging, the pooled prevalence of true unforeseen pN2 (9387 patients) was 7.97% (95% CI 6.67–9.27%), with a pooled OS after five years (892 patients) of 44% (95% CI 31–58%). Substantial heterogeneity regarding the characteristics of uN2 disease limited our meta-analysis considerably. However, it seems patients with uN2 disease represent a subcategory with a similar prognosis to stage IIb if complete surgical resection can be achieved, and the contribution of adjuvant therapy is to be further explored.