title: Tumour budding is a strong and independent prognostic factor in pancreatic cancer.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC.
  
  
  OBJECTIVE
  To assess the frequency and prognostic impact of tumour budding in PDAC.
  
  
  METHODS
  Whole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10buds across 10HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines.
  
  
  RESULTS
  Inter-observer agreement was considered strong (ICC=0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p=0.0463), lymphatic invasion (p=0.0192) and decreased disease-free (p=0.0005) and overall survival (p<0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p<0.0001; HR (95% CI): 3.65 (2.1-6.4)).
  
  
  CONCLUSIONS
  Our results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches.
authors.affiliation: Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, Switzerland. eva.diamantis@pathology.unibe.ch
authors.forename: E
authors.initials: E
authors.lastname: Karamitopoulou
authors.forename: I
authors.initials: I
authors.lastname: Zlobec
authors.forename: D
authors.initials: D
authors.lastname: Born
authors.forename: A
authors.initials: A
authors.lastname: Kondi-Pafiti
authors.forename: P
authors.initials: P
authors.lastname: Lykoudis
authors.forename: A
authors.initials: A
authors.lastname: Mellou
authors.forename: K
authors.initials: K
authors.lastname: Gennatas
authors.forename: B
authors.initials: B
authors.lastname: Gloor
authors.forename: A
authors.initials: A
authors.lastname: Lugli
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading / Q000379:methods; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis