title: Should the grading of colorectal adenocarcinoma include microsatellite instability status?
abstract: Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer-specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor.
authors.affiliation: Envoi Pathology, Brisbane, QLD 4059, Australia; University of Queensland, School of Medicine, Brisbane, QLD, 4029 Australia; Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton 3010, VIC, Australia. Electronic address: c.rosty@uq.edu.au.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Williamson
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton 3010, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Aung K
authors.initials: AK
authors.lastname: Win
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul 151-742, South Korea.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Genetic Medicine, The Royal Melbourne Hospital, Parkville, VIC 3010, Australia.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Winship
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton 3010, VIC, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3010, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3010, Australia.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton 3010, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology*; D045643:DNA Repair Enzymes / Q000032:analysis* / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D060787:Neoplasm Grading / Q000379:methods*; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D045643:DNA Repair Enzymes
keywords: Colorectal cancer; Grade; Microsatellite instability; Prognosis; Survival