Classic and Novel Histopathologic Risk Factors for Lymph Node Metastasis in T1 Colorectal Cancer: A Systematic Review and Meta-analysis

BACKGROUND: Treatment of endoscopically resected T1 colorectal cancers is based on the risk of lymph node metastasis. Risk is based on histopathologic features, although there is lack of consensus as to what constitutes high-risk features. OBJECTIVE: The purpose of this study was to conduct a systematic review and meta-analysis of histopathologic risk factors for lymph node metastasis. DATA SOURCES: A search of MEDLINE, Embase, Scopus, and Cochrane controlled register of trials for risk factors for lymph node metastasis was performed from inception until August 2018. STUDY SELECTION: Included patients must have had an oncologic resection to confirm lymph node status and reported at least 1 histopathologic risk factor. INTERVENTION: Rates of lymph node positivity were compared between patients with and without risk factors. MAIN OUTCOME MEASURES: We report the results of the meta-analysis as ORs. RESULTS: Of 8592 citations, 60 met inclusion criteria. Pooled analyses found that lymphovascular invasion, vascular invasion, neural invasion, and poorly differentiated histology were significantly associated with lymph node metastasis, as were depths of 1000 mu m (OR = 2.76), 1500 mu m (OR = 4.37), 2000 mu m (OR = 2.37), submucosal level 3 depth (OR = 3.08), and submucosal level 2/3 (OR = 3.08) depth. Depth of 3000 mu m, Haggitt level 4, and widths of 3000 mu m and 4000 mu m were not significantly associated with lymph node metastasis. Tumor budding (OR = 4.99) and poorly differentiated clusters (OR = 14.61) were also significantly associated with lymph node metastasis. LIMITATIONS: Included studies reported risk factors independently, making it impossible to examine the additive metastasis risk in patients with numerous risk factors. CONCLUSIONS: We identified 1500 mu m as the depth most significantly associated with lymph node metastasis. Novel factors tumor budding and poorly differentiated clusters were also significantly associated with lymph node metastasis. These findings should help inform guidelines regarding risk stratification of T1 tumors and prompt additional investigation into the exact contribution of poorly differentiated clusters to lymph node metastasis.