title: Tumor Budding in Colorectal Carcinoma: Confirmation of Prognostic Significance and Histologic Cutoff in a Population-based Cohort.
abstract: Tumor budding in colorectal carcinoma has been associated with poor outcome in multiple studies, but the absence of an established histologic cutoff for "high" tumor budding, heterogeneity in study populations, and varying methods for assessing tumor budding have hindered widespread incorporation of this parameter in clinical reports. We used an established scoring system in a population-based cohort to determine a histologic cutoff for "high" tumor budding and confirm its prognostic significance. We retrieved hematoxylin and eosin-stained sections from 553 incident colorectal carcinoma cases. Each case was previously characterized for select molecular alterations and survival data. Interobserver agreement was assessed between 2 gastrointestinal pathologists and a group of 4 general surgical pathologists. High budding (≥ 10 tumor buds in a ×20 objective field) was present in 32% of cases, low budding in 46%, and no budding in 22%. High tumor budding was associated with advanced pathologic stage (P < 0.001), microsatellite stability (P = 0.005), KRAS mutation (P = 0.010), and on multivariate analysis with a > 2 times risk of cancer-specific death (hazard ratio = 2.57 [1.27, 5.19]). After multivariate adjustment, by penalized smoothing splines, we found increasing tumor bud counts from 5 upward to be associated with an increasingly shortened cancer-specific survival. By this method, a tumor bud count of 10 corresponded to approximately 2.5 times risk of cancer-specific death. The interobserver agreement was good with weighted κ of 0.70 for 2 gastrointestinal pathologists over 121 random cases and 0.72 between all 6 pathologists for 20 random cases. Using an established method to assess budding on routine histologic stains, we have shown that a cutoff of 10 for high tumor budding is independently associated with a significantly worse prognosis. The reproducibility data provide support for the routine widespread implementation of tumor budding in clinical reports.
authors.affiliation: *Division of Anatomic Pathology †Department of Health Sciences Research ‡Division of Experimental Pathology #Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN §Van Andel Research Institute, Grand Rapids, MI ∥University of Southern California, USC/Norris Comprehensive Cancer Center, Los Angeles, CA ¶Department of Epidemiology, The University of Iowa, Iowa City, IA.
authors.forename: Rondell P
authors.initials: RP
authors.lastname: Graham
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Lori S
authors.initials: LS
authors.lastname: Tillmans
authors.forename: Alice H
authors.initials: AH
authors.lastname: Wang
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Yassaman
authors.initials: Y
authors.lastname: Raissian
authors.forename: Joaquin J
authors.initials: JJ
authors.lastname: Garcia
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kerr
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002277:Carcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D015588:Observer Variation; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015203:Reproducibility of Results; D012307:Risk Factors; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins