title: Comprehensive assessment of tumour budding by cytokeratin staining in colorectal cancer.
abstract: OBJECTIVE
  Tumour budding in colorectal cancer (CRC) is a recognized prognostic parameter. The aim of this study was to address the use of cytokeratin immunostaining for the visualization and scoring of tumour buds.
  
  
  RESULTS
  Ten hotspots (0.238 mm2) of peritumoural budding (PTB) and intratumoural budding (ITB) were evaluated in surgical resections from 215 patients. The budding counts in the 10 densest regions anywhere in the tumour were combined into an overall tumour budding (OTB) score. The PTB, ITB and OTB hotspot with the maximum budding count was then evaluated. Finally, continuous and cut-off values of 10 buds per high-power field (HPF) (PTB10HPF), five buds per HPF (ITB10HPF) and eight buds per HPF (OTB10HPF) were used to categorize budding counts into low-grade and high-grade scores. All budding scores were highly correlated. PTB and ITB counts were associated with many clinicopathological features, including tumour stage, lymph node and distant metastasis, venous and lymphovascular invasion, and disease-free survival (DFS) (all P < 0.05). Analyses of OTB counts recapitulated these associations, including a lower DFS with a greater number of tumour buds (P = 0.0309; hazard ratio 1.0332, 95% confidence interval 1.003-1.062). One OTB hotspot performed similarly to 10 OTB hotspots in terms of relationship with outcome. These statistical significances were largely lost when cut-offs were applied to PTB, ITB or OTB counts.
  
  
  CONCLUSIONS
  An OTB count in a single hotspot on cytokeratin-stained CRC tissue sections is a fast and reliable prognostic scoring system for the assessment of tumour budding. This approach should be considered in future studies.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Gregor
authors.initials: G
authors.lastname: Rieger
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.|Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.
authors.forename: Viktor H
authors.identifier: http://orcid.org/0000-0001-9206-4885
authors.initials: VH
authors.lastname: Koelzer
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Dawson
authors.affiliation: Department of Medical Oncology, Bern University Hospital, Bern, Switzerland.|Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Berger
authors.affiliation: Departments of Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Hädrich
authors.affiliation: Departments of Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland.|Department of Surgery, Bürgerspital Solothurn, Solothurn, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Inderbitzin
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D015179:Colorectal Neoplasms / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D053208:Kaplan-Meier Estimate; D007633:Keratins / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013194:Staining and Labeling
chemical_list: D014408:Biomarkers, Tumor; D007633:Keratins
keywords: colorectal cancer; pathology; precision medicine; prognosis