Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer

Abstract

Background:Tumour budding is a histological finding in epithelial cancers indicating an unfavourable phenotype. Previous studies have demonstrated that it is a negative prognostic indicator in colorectal cancer (CRC), and has been proposed as an additional factor to incorporate into staging protocols.Methods:A systematic review of papers until March 2016 published on Embase, Medline, PubMed, PubMed Central and Cochrane databases pertaining to tumour budding in CRC was performed. Study end points were the presence of lymph node metastases, recurrence (local and distal) and 5-year cancer-related death.Results:A total of 7821 patients from 34 papers were included, with a mean rate of tumour budding of 36.8±16.5%. Pooled analysis suggested that specimens exhibiting tumour budding were significantly associated with lymph node positivity (OR 4.94, 95% CI 3.96–6.17, P<0.00001), more likely to develop disease recurrence over the time period (OR 5.50, 95% CI 3.64–8.29, P<0.00001) and more likely to lead to cancer-related death at 5 years (OR 4.51, 95% CI 2.55–7.99, P<0.00001).Conclusions:Tumour budding in CRC is strongly predictive of lymph node metastases, recurrence and cancer-related death at 5 years, and its incorporation into the CRC staging algorithm will contribute to more effective risk stratification.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

“…1,5 . The prognostic power of tumor budding is not affected by the number of cells that defines a cluster 11,[13][14][15]18 . Since 4 tumor cells is the most widely used cut-off for tumor budding, and since this cut-off distinguishes tumor budding from the novel histopathological parameter "poorly differentiated cluster (PDC)" which is defined as 5 or more cells 27,59 , the ITBCC group agreed on a cut-off of up to 4 cells to define tumor budding reported, in accordance with current guidelines and protocols [69][70][71] .…”

“…field" and "10 high power field" methods) [11][12][13][14][15][16]18 . Counting across multiple fields has the advantage of being more representative of the entire invasive front, and there is also some evidence of improved inter-observer agreement using this approach [11][12][13][14][15][16]18,45 . On the other hand, counting multiple fields may "dilute" the final (mean) tumor bud count in cases with focally many tumor buds The "hotspot" method therefore better reflects the maximal extent of tumor budding at the invasive front.…”

“…Tumor budding is an independent adverse prognostic factor in colorectal cancer [11][12][13][14][15] . It is also associated with a higher TNM stage, high tumor grade, the presence of lymphovascular invasion and consequently with lymph node and distant metastases [11][12][13][14][15] .…”

“…It is also associated with a higher TNM stage, high tumor grade, the presence of lymphovascular invasion and consequently with lymph node and distant metastases [11][12][13][14][15] . In colorectal cancer, tumor budding can potentially be applied as an additional quantitative prognostic factor to facilitate the management of colorectal cancer patients in three clinical scenarios.…”

“…The selection of the tumor slide, the location of counting, the applied stain (H&E vs immunohistochemistry) and the scoring system (cut-off vs continuous scale) are practical points that need to be clarified and then validated in multiple studies. Nevertheless, tumor budding seems to be a robust biomarker which retains its prognostic value independently of selected scoring systems used in different studies [11][12][13][14][15] . The primary objective of the International Tumor Budding Consensus Conference (ITBCC), which took place in Bern in April 2016, was to reach agreement on an evidence-based, standardized scoring system for tumor budding to be used in international colorectal cancer guidelines and routine practice.…”