Abstract
Background
Infiltrative growth pattern at the tumor margin has been associated with shorter patient survival. However, little is known about the prognostic significance of tumor growth pattern, independent of tumoral molecular alterations and other histologic features.
Methods
Utilizing a database of 1139 colon and rectal cancer patients in two prospective cohort studies, histologic features including tumor growth pattern, tumor differentiation, lymphocytic reaction, mucinous component, and signet ring cell component were recorded by a single pathologist. Cox proportional hazard model was used to compute mortality hazard ratio, adjusting for clinical, pathologic, and tumor molecular features, including microsatellite instability, the CpG island methylator phenotype, long interspersed nucleotide element 1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutations.
Results
Among 1139 colorectal cancers, we observed expansile growth pattern in 372 tumors (33%), intermediate growth pattern in 610 tumors (54%), and infiltrative growth pattern in 157 tumors (14%). Compared to patients with expansile growth pattern, those with infiltrative growth pattern experienced shorter cancer-specific survival (log rank P < 0.0001; multivariate hazard ratio 1.74; 95% confidence interval 1.22–2.47) and overall survival (log rank P < 0.0001; multivariate hazard ratio 1.78; 95% confidence interval 1.33–2.39). The prognostic association of infiltrative growth pattern was confined to patients with stage I–III disease (P interaction with stage = 0.0001).
Conclusions
Infiltrative growth pattern was associated with worse prognosis among stage I–III colorectal cancer patients, independent of other clinical, pathologic, and molecular characteristics.
Similar content being viewed by others
References
Zlobec I, Lugli A. Invasive front of colorectal cancer: dynamic interface of pro-/anti-tumor factors. World J Gastroenterol. 2009;15:5898–906.
Jass JR, Atkin WS, Cuzick J, Bussey HJ, Morson BC, Northover JM, Todd IP. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology. 1986;10:437–59.
Jass JR, Love SB, Northover JM. A new prognostic classification of rectal cancer. Lancet. 1987;1:1303–6.
Halvorsen TB, Seim E. Association between invasiveness, inflammatory reaction, desmoplasia and survival in colorectal cancer. J Clin Pathol. 1989;42:162–6.
Shepherd NA, Saraga EP, Love SB, Jass JR. Prognostic factors in colonic cancer. Histopathology. 1989;14:613–20.
Kubota Y, Petras RE, Easley KA, Bauer TW, Tubbs RR, Fazio VW. Ki-67-determined growth fraction versus standard staging and grading parameters in colorectal carcinoma. A multivariate analysis. Cancer. 1992;70:2602–9.
Roncucci L, Fante R, Losi L, et al. Survival for colon and rectal cancer in a population-based cancer registry. Eur J Cancer. 1996;32A:295–302.
Cianchi F, Messerini L, Palomba A, et al. Character of the invasive margin in colorectal cancer: does it improve prognostic information of Dukes staging? Dis Colon Rectum. 1997;40:1170–5.
Cianchi F, Messerini L, Comin CE, et al. Pathologic determinants of survival after resection of T3N0 (stage IIA) colorectal cancer: proposal for a new prognostic model. Dis Colon Rectum. 2007;50:1332–41.
Zlobec I, Baker K, Minoo P, Hayashi S, Terracciano L, Lugli A. Tumor border configuration added to TNM staging better stratifies stage II colorectal cancer patients into prognostic subgroups. Cancer. 2009;115:4021–9.
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.
Pages F, Kirilovsky A, Mlecnik B, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009;27:5944–51.
Ogino S, Nosho K, Irahara N, et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009;15:6412–20.
Nosho K, Baba Y, Tanaka N, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222:350–66.
Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610–8.
Greenson JK, Bonner JD, Ben-Yzhak O, et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563–70.
Colomer A, Erill N, Vidal A, et al. A novel logistic model based on clinicopathological features predicts microsatellite instability in colorectal carcinomas. Diagn Mol Pathol. 2005;14:213–23.
Halvarsson B, Anderson H, Domanska K, Lindmark G, Nilbert M. Clinicopathologic factors identify sporadic mismatch repair–defective colon cancers. Am J Clin Pathol. 2008;129:238–44.
Greenson JK, Huang SC, Herron C, et al. Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol. 2009;33:126–33.
Roman R, Verdu M, Calvo M, et al. Microsatellite instability of the colorectal carcinoma can be predicted in the conventional pathologic examination. A prospective multicentric study and the statistical analysis of 615 cases consolidate our previously proposed logistic regression model. Virchows Arch. 2010;456:533–41.
Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.
Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–87e3.
Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356:2131–42.
Morikawa T, Kuchiba A, Yamauchi M, et al. Association of CTNNB1 (beta-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer. JAMA. 2011;305:1685–94.
Ogino S, Kawasaki T, Brahmandam M, et al. Sensitive sequencing method for KRAS mutation detection by pyrosequencing. J Mol Diagn. 2005;7:413–21.
Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS. CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn. 2006;8:582–8.
Ogino S, Nosho K, Kirkner GJ, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009;27:1477–84.
Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009;58:90–6.
Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M, Fuchs CS. Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn. 2007;9:305–14.
Nosho K, Irahara N, Shima K, et al. Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One. 2008;3:e3698.
Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–93.
Ogino S, Kawasaki T, Nosho K, et al. LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int J Cancer. 2008;122:2767–73.
Ogino S, Nosho K, Kirkner GJ, et al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst. 2008;100:1734–8.
Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer. 2000;88:1739–57.
Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma. 2nd ed. Tokyo: Kanehara, 2009.
Dundas SA, Laing RW, O’Cathain A, et al. Feasibility of new prognostic classification for rectal cancer. J Clin Pathol. 1988;41:1273–6.
Chu D, Li Y, Wang W, et al. High level of Notch1 protein is associated with poor overall survival in colorectal cancer. Ann Surg Oncol. 2010;17:1337–42.
Huh JW, Kim HR, Kim YJ. Prognostic value of perineural invasion in patients with stage II colorectal cancer. Ann Surg Oncol. 2010;17:2066–72.
Muratore A, Ribero D, Zimmitti G, Mellano A, Langella S, Capussotti L. Resection margin and recurrence-free survival after liver resection of colorectal metastases. Ann Surg Oncol. 2010;17:1324–9.
Kang H, Min BS, Lee KY, et al. Loss of E-cadherin and MUC2 expressions correlated with poor survival in patients with stages II and III colorectal carcinoma. Ann Surg Oncol. 2011;18:711–9.
Li D, Peng X, Yan D, et al. Msi-1 is a predictor of survival and a novel therapeutic target in colon cancer. Ann Surg Oncol. 2011;18:2074–83.
Samowitz WS, Albertsen H, Herrick J, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129:837–45.
Samowitz WS, Sweeney C, Herrick J, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65:6063–9.
Harrison JC, Dean PJ, el-Zeky F, Vander Zwaag R. From Dukes through Jass: pathological prognostic indicators in rectal cancer. Hum Pathol. 1994;25:498–505.
Farina-Sarasqueta A, van Lijnschoten G, Moerland E, et al. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 2010;21:2396–402.
Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011;104:856–62.
Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.
Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219–26.
Acknowledgment
We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. This work was supported by U.S. National Institute of Health (NIH) grants P01 CA87969 (to S. Hankinson), P01 CA55075 (to W. Willett), P50 CA127003 (to C.S.F.), and R01 CA151993 (to S.O.) and by grants from the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. T.M. was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
The first three authors contributed equally to this study.
Rights and permissions
About this article
Cite this article
Morikawa, T., Kuchiba, A., Qian, Z.R. et al. Prognostic Significance and Molecular Associations of Tumor Growth Pattern in Colorectal Cancer. Ann Surg Oncol 19, 1944–1953 (2012). https://doi.org/10.1245/s10434-011-2174-5
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-011-2174-5